J Huazhong Univ Sci Technol［Med Sci］ 34(5):701-705,2014 DOI 10.1007/s11596-014-1339-4 J Huazhong Univ Sci Technol［Med Sci］ 34(5):2014
701
Surgical Treatment of Chronic Pancreatitis in Young Patients Feng ZHOU (周 峰)†, Shan-miao GOU (勾善淼)†, Jiong-xin XIONG (熊炯炘), He-shui WU (吴河水), Chun-you WANG (王春友), Tao LIU (刘 涛)# Pancreatic Disease Institute, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China © Huazhong University of Science and Technology and Springer-Verlag Berlin Heidelberg 2014
Summary: The main treatment strategies for chronic pancreatitis in young patients include therapeutic endoscopic retrograde cholangio-pancreatography (ERCP) intervention and surgical intervention. Therapeutic ERCP intervention is performed much more extensively for its minimally invasive nature, but a part of patients are referred to surgery at last. Historical and follow-up data of 21 young patients with chronic pancreatitis undergoing duodenum-preserving total pancreatic head resection were analyzed to evaluate the outcomes of therapeutic ERCP intervention and surgical intervention in this study. The surgical complications of repeated therapeutic ERCP intervention and surgical intervention were 38% and 19% respectively. During the first therapeutic ERCP intervention to surgical intervention, 2 patients developed diabetes, 5 patients developed steatorrhea, and 5 patients developed pancreatic type B pain. During the follow-up of surgical intervention, 1 new case of diabetes occurred, 1 case of steatorrhea recovered, and 4 cases of pancreatic type B pain were completely relieved. In a part of young patients with chronic pancreatitis, surgical intervention was more effective than therapeutic ERCP intervention on delaying the progression of the disease and relieving the symptoms. Key words: chronic pancreatitis; duodenum-preserving total pancreatic head resection; endoscopic retrograde cholangio-pancreatography
Chronic pancreatitis (CP) is a continuing inflammatory disease of the pancreas characterized by irreversible morphologic changes that typically cause permanent loss of function and chronic disabling pain[1, 2]. Alcohol abuse is the most common cause of CP in adults in developed countries, while anatomic defects, hereditary diseases and biliary diseases predominate in children and adolescents[3, 4]. Most young patients with CP manifest as recurrent acute pancreatitis (RAP) at the onset of the disease. Mechanical obstruction of the main pancreatic duct is one of the major inciting factors for acute attacks of pancreatitis and fibrosis of parenchyma in these patients[5]. Some obstructive pathogenic factors such as pancreas divisum, sphincter of Oddi disorders and bile stones are presumed to be the root causes of the disease in some patients[4], and the other factors such as stones and protein plugs are formed during the pathologic process[6]. To prevent the acute attack of pancreatitis and alter the natural history of the disease, therapeutic endoscopic retrograde cholangio-pancreatography (ERCP) interventions were performed widely to remove the pathogenic factors in recent decades[7, 8]. According to previous reports and our experiences, therapeutic ERCP interventions including stone extraction, sphincterotomy and stent placement are effective for acute attacks of pancreatitis which offers immediate pain relief in most patients[9, 10]. However, it Feng ZHOU, E-mail: [email protected]; Shan-miao GOU, E-mail: [email protected] † The authors contribute equally to this work. # Corresponding author, E-mail: [email protected]
must be pointed out that some patients suffer acute attack of pancreatitis again in a short term after therapeutic ERCP interventions for the development of recurrence of obstruction, which is probably due to occluded or migrated stents, residue or recurrence of stones and protein plugs, etc.[11–13]. Therefore, these patients must be treat with repeat therapeutic ERCP interventions. In a small proportion of these patients, the disease progresseds into CP at last[14]. To completely eradicate the obstructive factors of the periampullary region and prevent the progression of the disease, we performed a duodenum-preserving total pancreatic head resection (DPPtHR) procedure on these patients. In this paper we report the outcomes of 21 young patients with CP who underwent DPPtHR procedure. All these patients received repeat therapeutic ERCP interventions before surgery. Results showed that this surgical procedure offered favorable short-term and long-term outcomes with acceptable morbidity compared with previous therapeutic ERCP interventions. 1 MATERIALS AND METHODS 1.1 Patients Forty-three young patients (less than 30 years old) with CP were treated in Pancreatic Center, Union Hospital, Wuhan, from January 1997 to June 2007. Twenty-one of these patients (8 males and 13 females, aged from 16 to 27 years old, mean age 21 years) who were treated with surgical intervention of DPPtHR procedure were involved in this study. Of these 21 patients, pancreatic divisum was present in 5 patients, sphincter of
702 Oddi dysfunction in 6 patients, and choledocholithiasis or microlithiasis in 6 patients. In the rest 4 patients, no pathogenic factors of CP were found. All patients had been treat with repeated therapeutic ERCP interventions before surgical intervention. For the progression of inflammation of the pancreas (especially the pancreatic head) and development of severe complications was not prevented by therapeutic ERCP intervention, these patients were treated with surgery at last. The main indications for surgery in these patients were as follows: (1) frequent acute attacks of pancreatitis; (2) progression of pancreatic parenchymal fibrosis and calcification; and (3) multiple stones that could not be removed by therapeutic ERCP intervention. The preoperative work-up included history, physical examination, routine laboratory testing, chest radiography, electrocardiography, contrast-enhanced computed tomography (CT), magnetic resonance imaging (MRI) and ERCP. Angiography and magnetic resonance angiography (MRA) were performed both preoperatively and postoperatively to evaluate pancreaticoduodenal arcades. Intraoperative frozen section and postoperative paraffin-embedded section investigations were used for confirmation of diagnosis. 1.2 Surgical Treatment The main indications for young patients with CP in our hospital were frequent acute attacks of pancreatitis and local complications that could not be removed by therapeutic ERCP intervention as described above. The chronic disabling pain, a main indication of surgical treatment for adult CP[15], was relatively less in young patients. The surgical technique used in our hospital was a modified DPPtHR procedure based on Beger’s procedure (duodenum-preserving subtotal pancreatic head resection)[16]. The main difference between our modified procedure and Beger’s procedure was the total resection of pancreatic head without segment resection of the duodenum[17]. Briefly, the anterior superior pancreaticoduodenal artery (ASPDA) was exposed and pushed towards the duodenal wall to make the section line of duodenal edge clearly. The portal vein was tunneled below the neck of the pancreas, and then the pancreatic head was transected on the duodenal edge of the portal vein. The pancreatic head was rotated to the left to expose the head mass and the uncinate process for resection. The pancreatic head and uncinate were resected to the duodenal wall along the interstice between the superior mesenteric artery and the duodenal edge of the portal vein. The jejunum was transected about 30 cm from the ligament of Treitz. The gastrointestinal tract was reconstructed with two anastomoses: (1) an anastomosis of the distal pancreas and the jejunum, and (2) an end-to-side anastomosis of the proximal jejunum and the distal jejunum. The preservation of the posterior pancreaticoduodenal arcade running parallel to the duodenum was essential for blood supply of the duodenum in this procedure. If possible, ASPDA was also preserved. Transection of the common bile duct and additional anastomosis of the common bile duct and the duodenum were performed on one patient for common bile duct stenosis that could not be resolved by resection of the pancreatic head. 1.3 Pain Status and Endocrine and Exocrine Function Pain status was estimated with 3 parameters, i.e. type of abdominal pain, frequency of analgesic medica-
J Huazhong Univ Sci Technol［Med Sci］ 34(5):2014
tion and the pain scale of EORTC QLQ-C30. The pain types were classified as type A and type B by Amman and colleagues[18]. Type A pain was characterized by recurrent bouts of short-term, relapsing pain episodes, and type B pain by prolonged and persistent pain. Frequency of analgesic medication was classified as none, occasional (taking medicine when pain attacks), and regular. As for EORTC QLQ-C30 pain scale, patients were asked to fill up a questionnaire before surgery, short term after surgery (at discharge) and long term (21–114 months, median 53 months) after surgery. Following the scoring instructions given by the EORTC Quality of Life Study group, the answers of patients were transformed to raw scores, then raw EORTC QLQ-C30 scores were linearly transformed to 0–100 scales before statistical analyses were performed. A higher score on pain scale represented more symptomatology[19]. A mean change ≥ 10 was regarded as clinically significant, as previously described[20]. For measurement of the endocrine function, an oral glucose tolerance test (OGTT) was performed. The grading of the endocrine function was as follows: “normal” if the glucose tolerance was within the normal range; “IGT” for impaired glucose tolerance; “diabetes” for manifest diabetes with need of antidiabetic medication. For rough measurement of the exocrine function, stool examination for fat absorption was performed. Stool fat > 6 g or fat absorption rate < 95% was considered as presence of steatorrhea. In addition, the short-term and long-term postoperative weight changes of patients were followed up. To reduce the effects of growth and development on weight change, we only evaluated the data of 10 patients over 22 years old when they received surgical treatment. 2 RESULTS 2.1 Preoperative Course All the 21 patients had been performed with repeat therapeutic ERCP interventions before surgical intervention. Nineteen patients were diagnosed as RAP and the rest 2 patients as CP at their first therapeutic ERCP intervention. The main indications for their first therapeutic ERCP intervention were congenital abnormalities of the periampullary region, sphincter of Oddi dysfunction and stones and protein plugs in the pancreatic main duct. Repeated therapeutic ERCP interventions were performed for recurrences. These 21 patients received a total of 103 therapeutic ERCP interventions (average 4.90, range 3 to 11) with 8 short-term complications (6 cases of post-ERCP pancreatitis, 1 case of infection and 1 case of bleeding). The total hospital stay of each patient for repeated therapeutic ERCP interventions was 14±10 days. The mortality was 0. Although receiving repeated therapeutic ERCP interventions, the inflammation of the pancreas (especially the pancreatic head) progressed and severe complications developed. In these patients, 8 developed pancreatic ductal stones and protein plugs, and 14 developed parenchymal fibrosis and calcification. Besides, 6 showed dilatation of the pancreatic main duct, 4 patients showed cholestasis, 2 developed diabetes, 5 developed steatorrhea, and 5 developed pancreatic type B pain (table 1). Thus they were treated with surgical intervention at last.
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J Huazhong Univ Sci Technol［Med Sci］ 34(5):2014
Table 1 Historical and follow-up data of patients* [n(%)] Before the first Preoperative Early postoperaERCP† stage‡ tive stage§
Late postoperative stage||
Pain status Pain type None 0 (0%) 0 (0%) 20 (95%) 17 (81%) Type A 21 (100%) 16 (76%) 0 (0%) 3 (14%) Type B 0 (0%) 5 (24%) 1 (5%) 1 (5%) Analgesic medication None 3 (14%) 0 (54%) 20 (95%) 18 (86%) Occasional 18 (86%) 19 (90%) 1 (5%) 3 (14%) Regular 0 (0%) 2 (10%) 0 (0%) 0 (0%) QLQ-C30 pain scale (Mean ± SD) / 46 ± 22 2±7 8 ± 18 Endocrine function OGTT Normal 16 (76%) 12 (57%) 13 (62%) 13 (62%) IGT 0 (0%) 7 (33%) 6 (29%) 5 (24%) Diabetes 0 (0%) 2 (10%) 2 (10%) 3 (14%) Not known 5 (24%) 0 (0%) 0 (0%) 0 (0%) Exocrine function Stool examination Normal 10 (48%) 16 (76%) 16 (76%) 17 (81%) Steatorrhea 0 (0%) 5 (24%) 5 (24%) 4 (19%) Not known 11 (52%) 0 (0%) 0 (0%) 0 (0%) Postoperative weight loss¶ / / / 0 (0%) Postoperative weight gain¶ / / / 3 (40%) * For postoperative weight loss, n=10; for others, n=21. † According to historical data. ‡ Before surgical intervention performed (median 47 months after the first ERCP). § At discharge after receiving surgical intervention. || According to the data of the last follow-up (21–114 months after surgical intervention, median 53 months). ¶ More than 10% of the preoperative stage at the last follow-up.
2.2 Intraoperative Course, Surgical Complications and Hospital Stay Histopathologic examination of the resected specimen confirmed the diagnosis of CP in all these 21 patients. Surgical findings showed that the tissue inflammation was mainly present in the pancreatic head and the uncinate process, while no or mild inflammatory lesions developed in the detail of the pancreas. Six patients showed mild dilatation of the pancreatic main duct, but severe dilatation with parenchymal atrophy was not observed in these patients. Therefore, no longitudinal opening of the pancreatic duct was performed in the DPPtHR procedure. The mean operating time was 238±42 min, the mean pancreatic intensive care unit (PICU) stay was 2±1 days, and the mean hospital stay was 11±5 days. Four complications (2 cases of bile leakage, 1 case of abdominal hemorrhage and 1 case of pancreatic fistula) developed in all patients undergoing operation during the postoperative course, and these patients recovered with conservative treatment. The mortality of the surgical procedure was 0. No patient underwent re-operation. 2.3 Prognosis Postoperative pain status and endocrine and exocrine function were evaluated in this study. The data of short-term and long-term follow-up are listed in table 1. Before surgery, 16 patients suffered type A abdominal pain, while the rest 5 patients suffered type B. Of these patients, 2 required regular analgesic medication. The mean EORTC QLQ-C30 pain score was 46±22. After
surgery, almost all patients obtained immediate pain relief. In the late postoperative period, 17 patients obtained complete pain relief, 18 required no analgesic medication, and 3 patients required occasional analgesic medication to control pain. The mean EORTC QLQ-C30 pain score was decreased to 8±18. To estimate the endocrine and exocrine function roughly, OGTT and stool examination for fat absorption were performed on all patients. In addition, weight change was also followed up. OGTT showed that 7 patients had an IGT, and 2 patients were already diabetic prior to surgery. According to stool examination, 5 patients suffered steatorrhea, 3 of which had clinical symptoms or signs of steatorrhea. In the early and late postoperative stages, the endocrine and exocrine function of the patients was equal to the preoperative stage. Concerning the weight change, weight loss >10% at the preoperative stage was observed in the patients, while weight gain >10% was observed in 3 patients. 3 DISCUSSION RAP is generally defined as the presence of at least two documented episodes of acute pancreatitis occurring in a setting of a normal morpho-functional gland. Although the etiologies of RAP vary in young patients, it is believed that obstructive components involving the periampullary region may play an important role in the progression of the disease. These obstructive factors, including potential root pathogenic factors of the disease
704 (pancreas divisum, sphincter of Oddi disorders, bile stones, etc.) and stones/protein plugs in pancreatic ducts that developed during the process of the disease, can lead to acute attack of pancreatitis[21]. The treatment strategies for elimination of obstructive factors in RAP include therapeutic ERCP intervention and surgical intervention. Most surgeons propose therapeutic ERCP intervention for its minimally invasive nature, while surgical intervention, a more invasive strategy, is rarely used. According to previous reports and our experiences, therapeutic ERCP intervention offers immediate pain relief for acute attacks of pancreatitis in most patients. However, long-term follow-up showed that some patients suffered further acute attacks of pancreatitis after therapeutic ERCP intervention. The causes for recurrence include stent occlusion and migration, post-ERCP fibrosis and scarring of the pancreatic orifice, recurrence of pancreatic main ductal stones and protein plugs, etc.. In that case, further therapeutic ERCP intervention would be proposed to these patients routinely[22]. For RAP has been strictly divided from CP since the first Marseille classification of pancreatitis[23], and the progression of RAP to CP was considered to be extremely uncommon, the progression of the disease was overlooked in some cases, and some surgeons satisfied the short-term outcomes of repeat therapeutic ERCP interventions. However, although historically controversial, the association between RAP and CP has been established by clinicopathologic studies and animal studies[24, 25] . RAP can develop into CP over time if the pathogenic factors persist, and reports of lack of progression from RAP to CP can be explained by their limited follow-up. We slant towards this view because we found that most young patients with CP had a history of RAP. Of these 21 patients involved in this study, 19 patients were diagnosed with RAP but CP at their first visit to a doctor. Even the 2 patients diagnosed with early-stage CP at their first visit to a doctor had a history of repeated abdominal pain. To deal with the acute attacks of pancreatitis and prevent the recurrences, a total of 103 therapeutic ERCP interventions were performed on these patients to remove obstructive factors. However, the progression of the disease was not stopped. When referred to our center, these patients had developed irreversible chronic inflammatory changes of the pancreatic parenchyma (especially in the pancreatic head) and/or progressive pancreatic dysfunction. To prevent the recurrence of acute pancreatitis and the progression of the disease, surgical intervention of DPPtHR was performed on these patients to remove obstructive factors involving the periampullary region at last. The morbidity of post-operative complications of the surgical intervention was 19%, which was higher than that of single therapeutic ERCP intervention. However, for the repeat performance of therapeutic ERCP intervention, the overall morbidity of therapeutic ERCP intervention was higher (4/21 in DPPtHR vs. 10/21 in ERCP). Similarly, the mean hospital stay of surgical intervention was longer than that of single therapeutic ERCP intervention but shorter than that of summation of all therapeutic ERCP interventions (11±5 days in DPPtHR vs. 14±10 days in ERCP). Although surgical intervention of DPPtHR is more invasive than therapeu-
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tic ERCP intervention, the duodenum, which plays a crucial role in glucose metabolism, was preserved in DPPtHR procedure, and postoperative hypoglycemia, a poor prognostic factor of pancreatic surgery, was never observed. During the long-term follow-up period of an average 5 years after surgical intervention, 18 patients remained free of acute attacks of pancreatitis. Three patients suffered 4 acute attacks of pancreatitis, and these recurrences were treated conservatively. Type B pain is a characteristic of CP and hardly managed with therapeutic ERCP intervention, but it responds much better to surgical intervention. During the process of the disease, 5 patients developed type B pain. After treated with DPPtHR procedure, four but one patients obtained complete pain relief. Concerning the endocrine and exocrine function, the progression of pancreatic dysfunction was almost prevented, even those who developed clinical symptom of steatorrhea no longer need enzyme supplementation during the follow-up period. In conclusion, we reported the history and the follow-up data of 21 young patients with CP. Most of them manifested as RAP at the onset of the disease. All these patients were treated initially with therapeutic ERCP intervention, and surgical intervention was performed at last. Reviewing the treatment history of these patients, therapeutic ERCP intervention had an advantage of less invasion, but for its repeat performance, the overall morbidity and hospital stay were comparable to those of surgical interventions. Even more important, repeat therapeutic ERCP interventions did not stop the progression of the disease into CP in these patients and played little role in relief of type B pain, while DPPtHR offered satisfied effects for CP both on delay of disease progression and relief of type B pain. According to previous studies, most patients of RAP could obtain a favorable prognosis after removal of etiologic factors by therapeutic ERCP interventions. However, the acute attack of pancreatitis and the progression to CP could not be prevented in a small proportion of the patients. Twenty-one of these patients referred to our center were treated with surgical intervention at last. Although the DPPtHR procedure was effective for local complications and offered favorable prognosis for these patients, for its rigorous indications, most patients had developed pancreatic dysfunction, which never occurred at the onset of the disease, when they referred to surgery. The pancreatic dysfunction was hardly to recover and these patients would need lifelong insulin and enzyme supplementation. According to our experiences that the progression of the disease in postoperative stage was much slower than that in preoperative stage, we tentatively put forward that earlier surgical intervention on patients, in whom the progression of the disease can not be prevented by repeated therapeutic ERCP interventions, may offer better prognosis. But how to distinguish patients that will progress to CP from others in early stage, and what the proper indications for surgical intervention should be are still controversial issues that need further discussion. Conflict of Interest Statement The authors declare that there is no conflict of interest with any financial organization or corporation or individual that can inappropriately influence this work.
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REFERENCES 1 Ahmed SA, Wray C, Rilo HL, et al. Chronic pancreatitis: recent advances and ongoing challenges. Curr Probl Surg, 2006,43(3):127-238 2 Steer ML, Waxman I, Freedman S. Chronic pancreatitis. N Engl J Med, 1995,332(22):1482-1490 3 Ammann RW. A clinically based classification system for alcoholic chronic pancreatitis: summary of an international workshop on chronic pancreatitis. Pancreas, 1997,14(3): 215-221 4 Etemad B, Whitcomb DC. Chronic pancreatitis: diagnosis, classification, and new genetic developments. Gastroenterology, 2001,120(3):682-707 5 Stevens T, Conwell DL, Zuccaro G. Pathogenesis of chronic pancreatitis: an evidence-based review of past theories and recent developments. Am J Gastroenterol, 2004,99(11): 2256-2270 6 Ammann RW, Heitz PU, Kloppel G. Course of alcoholic chronic pancreatitis: a prospective clinicomorphological long-term study. Gastroenterology, 1996,111(1):224-231 7 Neuhaus H. Therapeutic pancreatic endoscopy. Endoscopy, 2004,36(1):8-16 8 Baillie J. Endoscopic therapy in acute recurrent pancreatitis. World J Gastroenterol, 2008,14(7):1034-1037 9 Morgan DE, Logan K, Baron TH, et al. Pancreas divisum: implications for diagnostic and therapeutic pancreatography. Am J Roentgenol, 1999,173(1):193-198 10 Testoni PA, Caporuscio S, Bagnolo F, et al. Idiopathic recurrent pancreatitis: long-term results after ERCP, endoscopic sphincterotomy, or ursodeoxycholic acid treatment. Am J Gastroenterol, 2000,95(7):1702-1707 11 Johanson JF, Schmalz MJ, Geenen JE. Incidence and risk factors for biliary and pancreatic stent migration. Gastrointest Endosc, 1992,38(3):341-346 12 Maydeo A, Soehendra N, Reddy N, et al. Endotherapy for chronic pancreatitis with intracanalar stones. Endoscopy, 2007,39(7):653-658 13 Smith MT, Sherman S, Ikenberry SO, et al. Alterations in pancreatic ductal morphology following polyethylene pancre-
705 atic stent therapy. Gastrointest Endosc, 1996,44(3):268-275 14 Mariani A, Testoni PA. Is acute recurrent pancreatitis a chronic disease? World J Gastroenterol, 2008,14(7):995-998 15 Gall FP, Muhe E, Gebhardt C. Results of partial and total pancreaticoduodenectomy in 117 patients with chronic pancreatitis. World J Surg, 1981,5(2):269-275 16 Beger HG, Krautzberger W, Bittner R, et al. Duodenum-preserving resection of the head of the pancreas in patients with severe chronic pancreatitis. Surgery, 1985,97(4): 467-473 17 Wang C, Liu T, Wu H, et al. Duodenum-preserving total pancreatic head resection without segment resection of the duodenum for chronic pancreatitis. Langenbecks Arch Surg, 2009,394(3):563-568 18 Ammann RW, Muellhaupt B. The natural history of pain in alcoholic chronic pancreatitis. Gastroenterology, 1999, 116(5):1132-1140 19 Sprangers MA, Cull A, Bjordal K, et al. The European Organization for Research and Treatment of Cancer. Approach to quality of life assessment: guidelines for developing questionnaire modules. EORTC Study Group on Quality of Life. Qual Life Res, 1993,2(4):287-295 20 Osoba D, Rodrigues G, Myles J, et al. Interpreting the significance of changes in health-related quality-of-life scores. J Clin Oncol, 1998,16(1):139-144 21 Delhaye M, Matos C, Arvanitakis M, et al. Pancreatic ductal system obstruction and acute recurrent pancreatitis. World J Gastroenterol, 2008,14(7):1027-1033 22 Cahen DL, Gouma DJ, Nio Y, et al. Endoscopic versus surgical drainage of the pancreatic duct in chronic pancreatitis. N Engl J Med, 2007,356(20):676-684 23 Sarles H, Bernard JP, Gullo L. Pathogenesis of chronic pancreatitis. Gut, 1990,31(6):629-632 24 Ammann RW, Muellhaupt B. Progression of alcoholic acute to chronic pancreatitis. Gut, 1994,35(4):552-556 25 Freiburghaus AU, Redha F, Ammann RW. Does acute pancreatitis progress to chronic pancreatitis? A microvascular pancreatitis model in the rat. Pancreas, 1995,11(4):374-381 (Received July 6, 2014; revised Aug. 14, 2014)
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Surgical Treatment of Chronic Pancreatitis in Young Patients Feng ZHOU (周 峰)†, Shan-miao GOU (勾善淼)†, Jiong-xin XIONG (熊炯炘), He-shui WU (吴河水), Chun-you WANG (王春友), Tao LIU (刘 涛)# Pancreatic Disease Institute, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China © Huazhong University of Science and Technology and Springer-Verlag Berlin Heidelberg 2014
Summary: The main treatment strategies for chronic pancreatitis in young patients include therapeutic endoscopic retrograde cholangio-pancreatography (ERCP) intervention and surgical intervention. Therapeutic ERCP intervention is performed much more extensively for its minimally invasive nature, but a part of patients are referred to surgery at last. Historical and follow-up data of 21 young patients with chronic pancreatitis undergoing duodenum-preserving total pancreatic head resection were analyzed to evaluate the outcomes of therapeutic ERCP intervention and surgical intervention in this study. The surgical complications of repeated therapeutic ERCP intervention and surgical intervention were 38% and 19% respectively. During the first therapeutic ERCP intervention to surgical intervention, 2 patients developed diabetes, 5 patients developed steatorrhea, and 5 patients developed pancreatic type B pain. During the follow-up of surgical intervention, 1 new case of diabetes occurred, 1 case of steatorrhea recovered, and 4 cases of pancreatic type B pain were completely relieved. In a part of young patients with chronic pancreatitis, surgical intervention was more effective than therapeutic ERCP intervention on delaying the progression of the disease and relieving the symptoms. Key words: chronic pancreatitis; duodenum-preserving total pancreatic head resection; endoscopic retrograde cholangio-pancreatography
Chronic pancreatitis (CP) is a continuing inflammatory disease of the pancreas characterized by irreversible morphologic changes that typically cause permanent loss of function and chronic disabling pain[1, 2]. Alcohol abuse is the most common cause of CP in adults in developed countries, while anatomic defects, hereditary diseases and biliary diseases predominate in children and adolescents[3, 4]. Most young patients with CP manifest as recurrent acute pancreatitis (RAP) at the onset of the disease. Mechanical obstruction of the main pancreatic duct is one of the major inciting factors for acute attacks of pancreatitis and fibrosis of parenchyma in these patients[5]. Some obstructive pathogenic factors such as pancreas divisum, sphincter of Oddi disorders and bile stones are presumed to be the root causes of the disease in some patients[4], and the other factors such as stones and protein plugs are formed during the pathologic process[6]. To prevent the acute attack of pancreatitis and alter the natural history of the disease, therapeutic endoscopic retrograde cholangio-pancreatography (ERCP) interventions were performed widely to remove the pathogenic factors in recent decades[7, 8]. According to previous reports and our experiences, therapeutic ERCP interventions including stone extraction, sphincterotomy and stent placement are effective for acute attacks of pancreatitis which offers immediate pain relief in most patients[9, 10]. However, it Feng ZHOU, E-mail: [email protected]; Shan-miao GOU, E-mail: [email protected] † The authors contribute equally to this work. # Corresponding author, E-mail: [email protected]
must be pointed out that some patients suffer acute attack of pancreatitis again in a short term after therapeutic ERCP interventions for the development of recurrence of obstruction, which is probably due to occluded or migrated stents, residue or recurrence of stones and protein plugs, etc.[11–13]. Therefore, these patients must be treat with repeat therapeutic ERCP interventions. In a small proportion of these patients, the disease progresseds into CP at last[14]. To completely eradicate the obstructive factors of the periampullary region and prevent the progression of the disease, we performed a duodenum-preserving total pancreatic head resection (DPPtHR) procedure on these patients. In this paper we report the outcomes of 21 young patients with CP who underwent DPPtHR procedure. All these patients received repeat therapeutic ERCP interventions before surgery. Results showed that this surgical procedure offered favorable short-term and long-term outcomes with acceptable morbidity compared with previous therapeutic ERCP interventions. 1 MATERIALS AND METHODS 1.1 Patients Forty-three young patients (less than 30 years old) with CP were treated in Pancreatic Center, Union Hospital, Wuhan, from January 1997 to June 2007. Twenty-one of these patients (8 males and 13 females, aged from 16 to 27 years old, mean age 21 years) who were treated with surgical intervention of DPPtHR procedure were involved in this study. Of these 21 patients, pancreatic divisum was present in 5 patients, sphincter of
702 Oddi dysfunction in 6 patients, and choledocholithiasis or microlithiasis in 6 patients. In the rest 4 patients, no pathogenic factors of CP were found. All patients had been treat with repeated therapeutic ERCP interventions before surgical intervention. For the progression of inflammation of the pancreas (especially the pancreatic head) and development of severe complications was not prevented by therapeutic ERCP intervention, these patients were treated with surgery at last. The main indications for surgery in these patients were as follows: (1) frequent acute attacks of pancreatitis; (2) progression of pancreatic parenchymal fibrosis and calcification; and (3) multiple stones that could not be removed by therapeutic ERCP intervention. The preoperative work-up included history, physical examination, routine laboratory testing, chest radiography, electrocardiography, contrast-enhanced computed tomography (CT), magnetic resonance imaging (MRI) and ERCP. Angiography and magnetic resonance angiography (MRA) were performed both preoperatively and postoperatively to evaluate pancreaticoduodenal arcades. Intraoperative frozen section and postoperative paraffin-embedded section investigations were used for confirmation of diagnosis. 1.2 Surgical Treatment The main indications for young patients with CP in our hospital were frequent acute attacks of pancreatitis and local complications that could not be removed by therapeutic ERCP intervention as described above. The chronic disabling pain, a main indication of surgical treatment for adult CP[15], was relatively less in young patients. The surgical technique used in our hospital was a modified DPPtHR procedure based on Beger’s procedure (duodenum-preserving subtotal pancreatic head resection)[16]. The main difference between our modified procedure and Beger’s procedure was the total resection of pancreatic head without segment resection of the duodenum[17]. Briefly, the anterior superior pancreaticoduodenal artery (ASPDA) was exposed and pushed towards the duodenal wall to make the section line of duodenal edge clearly. The portal vein was tunneled below the neck of the pancreas, and then the pancreatic head was transected on the duodenal edge of the portal vein. The pancreatic head was rotated to the left to expose the head mass and the uncinate process for resection. The pancreatic head and uncinate were resected to the duodenal wall along the interstice between the superior mesenteric artery and the duodenal edge of the portal vein. The jejunum was transected about 30 cm from the ligament of Treitz. The gastrointestinal tract was reconstructed with two anastomoses: (1) an anastomosis of the distal pancreas and the jejunum, and (2) an end-to-side anastomosis of the proximal jejunum and the distal jejunum. The preservation of the posterior pancreaticoduodenal arcade running parallel to the duodenum was essential for blood supply of the duodenum in this procedure. If possible, ASPDA was also preserved. Transection of the common bile duct and additional anastomosis of the common bile duct and the duodenum were performed on one patient for common bile duct stenosis that could not be resolved by resection of the pancreatic head. 1.3 Pain Status and Endocrine and Exocrine Function Pain status was estimated with 3 parameters, i.e. type of abdominal pain, frequency of analgesic medica-
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tion and the pain scale of EORTC QLQ-C30. The pain types were classified as type A and type B by Amman and colleagues[18]. Type A pain was characterized by recurrent bouts of short-term, relapsing pain episodes, and type B pain by prolonged and persistent pain. Frequency of analgesic medication was classified as none, occasional (taking medicine when pain attacks), and regular. As for EORTC QLQ-C30 pain scale, patients were asked to fill up a questionnaire before surgery, short term after surgery (at discharge) and long term (21–114 months, median 53 months) after surgery. Following the scoring instructions given by the EORTC Quality of Life Study group, the answers of patients were transformed to raw scores, then raw EORTC QLQ-C30 scores were linearly transformed to 0–100 scales before statistical analyses were performed. A higher score on pain scale represented more symptomatology[19]. A mean change ≥ 10 was regarded as clinically significant, as previously described[20]. For measurement of the endocrine function, an oral glucose tolerance test (OGTT) was performed. The grading of the endocrine function was as follows: “normal” if the glucose tolerance was within the normal range; “IGT” for impaired glucose tolerance; “diabetes” for manifest diabetes with need of antidiabetic medication. For rough measurement of the exocrine function, stool examination for fat absorption was performed. Stool fat > 6 g or fat absorption rate < 95% was considered as presence of steatorrhea. In addition, the short-term and long-term postoperative weight changes of patients were followed up. To reduce the effects of growth and development on weight change, we only evaluated the data of 10 patients over 22 years old when they received surgical treatment. 2 RESULTS 2.1 Preoperative Course All the 21 patients had been performed with repeat therapeutic ERCP interventions before surgical intervention. Nineteen patients were diagnosed as RAP and the rest 2 patients as CP at their first therapeutic ERCP intervention. The main indications for their first therapeutic ERCP intervention were congenital abnormalities of the periampullary region, sphincter of Oddi dysfunction and stones and protein plugs in the pancreatic main duct. Repeated therapeutic ERCP interventions were performed for recurrences. These 21 patients received a total of 103 therapeutic ERCP interventions (average 4.90, range 3 to 11) with 8 short-term complications (6 cases of post-ERCP pancreatitis, 1 case of infection and 1 case of bleeding). The total hospital stay of each patient for repeated therapeutic ERCP interventions was 14±10 days. The mortality was 0. Although receiving repeated therapeutic ERCP interventions, the inflammation of the pancreas (especially the pancreatic head) progressed and severe complications developed. In these patients, 8 developed pancreatic ductal stones and protein plugs, and 14 developed parenchymal fibrosis and calcification. Besides, 6 showed dilatation of the pancreatic main duct, 4 patients showed cholestasis, 2 developed diabetes, 5 developed steatorrhea, and 5 developed pancreatic type B pain (table 1). Thus they were treated with surgical intervention at last.
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Table 1 Historical and follow-up data of patients* [n(%)] Before the first Preoperative Early postoperaERCP† stage‡ tive stage§
Late postoperative stage||
Pain status Pain type None 0 (0%) 0 (0%) 20 (95%) 17 (81%) Type A 21 (100%) 16 (76%) 0 (0%) 3 (14%) Type B 0 (0%) 5 (24%) 1 (5%) 1 (5%) Analgesic medication None 3 (14%) 0 (54%) 20 (95%) 18 (86%) Occasional 18 (86%) 19 (90%) 1 (5%) 3 (14%) Regular 0 (0%) 2 (10%) 0 (0%) 0 (0%) QLQ-C30 pain scale (Mean ± SD) / 46 ± 22 2±7 8 ± 18 Endocrine function OGTT Normal 16 (76%) 12 (57%) 13 (62%) 13 (62%) IGT 0 (0%) 7 (33%) 6 (29%) 5 (24%) Diabetes 0 (0%) 2 (10%) 2 (10%) 3 (14%) Not known 5 (24%) 0 (0%) 0 (0%) 0 (0%) Exocrine function Stool examination Normal 10 (48%) 16 (76%) 16 (76%) 17 (81%) Steatorrhea 0 (0%) 5 (24%) 5 (24%) 4 (19%) Not known 11 (52%) 0 (0%) 0 (0%) 0 (0%) Postoperative weight loss¶ / / / 0 (0%) Postoperative weight gain¶ / / / 3 (40%) * For postoperative weight loss, n=10; for others, n=21. † According to historical data. ‡ Before surgical intervention performed (median 47 months after the first ERCP). § At discharge after receiving surgical intervention. || According to the data of the last follow-up (21–114 months after surgical intervention, median 53 months). ¶ More than 10% of the preoperative stage at the last follow-up.
2.2 Intraoperative Course, Surgical Complications and Hospital Stay Histopathologic examination of the resected specimen confirmed the diagnosis of CP in all these 21 patients. Surgical findings showed that the tissue inflammation was mainly present in the pancreatic head and the uncinate process, while no or mild inflammatory lesions developed in the detail of the pancreas. Six patients showed mild dilatation of the pancreatic main duct, but severe dilatation with parenchymal atrophy was not observed in these patients. Therefore, no longitudinal opening of the pancreatic duct was performed in the DPPtHR procedure. The mean operating time was 238±42 min, the mean pancreatic intensive care unit (PICU) stay was 2±1 days, and the mean hospital stay was 11±5 days. Four complications (2 cases of bile leakage, 1 case of abdominal hemorrhage and 1 case of pancreatic fistula) developed in all patients undergoing operation during the postoperative course, and these patients recovered with conservative treatment. The mortality of the surgical procedure was 0. No patient underwent re-operation. 2.3 Prognosis Postoperative pain status and endocrine and exocrine function were evaluated in this study. The data of short-term and long-term follow-up are listed in table 1. Before surgery, 16 patients suffered type A abdominal pain, while the rest 5 patients suffered type B. Of these patients, 2 required regular analgesic medication. The mean EORTC QLQ-C30 pain score was 46±22. After
surgery, almost all patients obtained immediate pain relief. In the late postoperative period, 17 patients obtained complete pain relief, 18 required no analgesic medication, and 3 patients required occasional analgesic medication to control pain. The mean EORTC QLQ-C30 pain score was decreased to 8±18. To estimate the endocrine and exocrine function roughly, OGTT and stool examination for fat absorption were performed on all patients. In addition, weight change was also followed up. OGTT showed that 7 patients had an IGT, and 2 patients were already diabetic prior to surgery. According to stool examination, 5 patients suffered steatorrhea, 3 of which had clinical symptoms or signs of steatorrhea. In the early and late postoperative stages, the endocrine and exocrine function of the patients was equal to the preoperative stage. Concerning the weight change, weight loss >10% at the preoperative stage was observed in the patients, while weight gain >10% was observed in 3 patients. 3 DISCUSSION RAP is generally defined as the presence of at least two documented episodes of acute pancreatitis occurring in a setting of a normal morpho-functional gland. Although the etiologies of RAP vary in young patients, it is believed that obstructive components involving the periampullary region may play an important role in the progression of the disease. These obstructive factors, including potential root pathogenic factors of the disease
704 (pancreas divisum, sphincter of Oddi disorders, bile stones, etc.) and stones/protein plugs in pancreatic ducts that developed during the process of the disease, can lead to acute attack of pancreatitis[21]. The treatment strategies for elimination of obstructive factors in RAP include therapeutic ERCP intervention and surgical intervention. Most surgeons propose therapeutic ERCP intervention for its minimally invasive nature, while surgical intervention, a more invasive strategy, is rarely used. According to previous reports and our experiences, therapeutic ERCP intervention offers immediate pain relief for acute attacks of pancreatitis in most patients. However, long-term follow-up showed that some patients suffered further acute attacks of pancreatitis after therapeutic ERCP intervention. The causes for recurrence include stent occlusion and migration, post-ERCP fibrosis and scarring of the pancreatic orifice, recurrence of pancreatic main ductal stones and protein plugs, etc.. In that case, further therapeutic ERCP intervention would be proposed to these patients routinely[22]. For RAP has been strictly divided from CP since the first Marseille classification of pancreatitis[23], and the progression of RAP to CP was considered to be extremely uncommon, the progression of the disease was overlooked in some cases, and some surgeons satisfied the short-term outcomes of repeat therapeutic ERCP interventions. However, although historically controversial, the association between RAP and CP has been established by clinicopathologic studies and animal studies[24, 25] . RAP can develop into CP over time if the pathogenic factors persist, and reports of lack of progression from RAP to CP can be explained by their limited follow-up. We slant towards this view because we found that most young patients with CP had a history of RAP. Of these 21 patients involved in this study, 19 patients were diagnosed with RAP but CP at their first visit to a doctor. Even the 2 patients diagnosed with early-stage CP at their first visit to a doctor had a history of repeated abdominal pain. To deal with the acute attacks of pancreatitis and prevent the recurrences, a total of 103 therapeutic ERCP interventions were performed on these patients to remove obstructive factors. However, the progression of the disease was not stopped. When referred to our center, these patients had developed irreversible chronic inflammatory changes of the pancreatic parenchyma (especially in the pancreatic head) and/or progressive pancreatic dysfunction. To prevent the recurrence of acute pancreatitis and the progression of the disease, surgical intervention of DPPtHR was performed on these patients to remove obstructive factors involving the periampullary region at last. The morbidity of post-operative complications of the surgical intervention was 19%, which was higher than that of single therapeutic ERCP intervention. However, for the repeat performance of therapeutic ERCP intervention, the overall morbidity of therapeutic ERCP intervention was higher (4/21 in DPPtHR vs. 10/21 in ERCP). Similarly, the mean hospital stay of surgical intervention was longer than that of single therapeutic ERCP intervention but shorter than that of summation of all therapeutic ERCP interventions (11±5 days in DPPtHR vs. 14±10 days in ERCP). Although surgical intervention of DPPtHR is more invasive than therapeu-
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tic ERCP intervention, the duodenum, which plays a crucial role in glucose metabolism, was preserved in DPPtHR procedure, and postoperative hypoglycemia, a poor prognostic factor of pancreatic surgery, was never observed. During the long-term follow-up period of an average 5 years after surgical intervention, 18 patients remained free of acute attacks of pancreatitis. Three patients suffered 4 acute attacks of pancreatitis, and these recurrences were treated conservatively. Type B pain is a characteristic of CP and hardly managed with therapeutic ERCP intervention, but it responds much better to surgical intervention. During the process of the disease, 5 patients developed type B pain. After treated with DPPtHR procedure, four but one patients obtained complete pain relief. Concerning the endocrine and exocrine function, the progression of pancreatic dysfunction was almost prevented, even those who developed clinical symptom of steatorrhea no longer need enzyme supplementation during the follow-up period. In conclusion, we reported the history and the follow-up data of 21 young patients with CP. Most of them manifested as RAP at the onset of the disease. All these patients were treated initially with therapeutic ERCP intervention, and surgical intervention was performed at last. Reviewing the treatment history of these patients, therapeutic ERCP intervention had an advantage of less invasion, but for its repeat performance, the overall morbidity and hospital stay were comparable to those of surgical interventions. Even more important, repeat therapeutic ERCP interventions did not stop the progression of the disease into CP in these patients and played little role in relief of type B pain, while DPPtHR offered satisfied effects for CP both on delay of disease progression and relief of type B pain. According to previous studies, most patients of RAP could obtain a favorable prognosis after removal of etiologic factors by therapeutic ERCP interventions. However, the acute attack of pancreatitis and the progression to CP could not be prevented in a small proportion of the patients. Twenty-one of these patients referred to our center were treated with surgical intervention at last. Although the DPPtHR procedure was effective for local complications and offered favorable prognosis for these patients, for its rigorous indications, most patients had developed pancreatic dysfunction, which never occurred at the onset of the disease, when they referred to surgery. The pancreatic dysfunction was hardly to recover and these patients would need lifelong insulin and enzyme supplementation. According to our experiences that the progression of the disease in postoperative stage was much slower than that in preoperative stage, we tentatively put forward that earlier surgical intervention on patients, in whom the progression of the disease can not be prevented by repeated therapeutic ERCP interventions, may offer better prognosis. But how to distinguish patients that will progress to CP from others in early stage, and what the proper indications for surgical intervention should be are still controversial issues that need further discussion. Conflict of Interest Statement The authors declare that there is no conflict of interest with any financial organization or corporation or individual that can inappropriately influence this work.
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