遗传性胰腺炎发病机制及治疗研究进展

遗传性胰腺炎是急性或慢性胰腺炎的一种罕见类型,临床表现与其他原因所致胰腺炎类似。1996年Whitcomb首次报道PRSS1基因突变为遗传性胰腺炎的病因。随后SPINK1基因、CFTR基因、CTRC基因被报道与遗传性胰腺炎相关,但它们是否为遗传性胰腺炎的致病基因仍存在争议。PRSS1编码阳离子胰蛋白酶原,该基因的突变可能导致胰蛋白原激活增加或失活减少,引起临床胰腺炎。目前已经报道了超过20种PRSS1的致病性突变,其中最常见的突变位点为R122H、N29I、和A16V。遗传性胰腺炎发病年龄较早,通常在20岁前起病,平均发病年龄为10岁,进展为慢性胰腺炎的平均年龄为20岁,50岁以后胰腺癌发病风险明显增加。遗传性胰腺炎患者的监管包括:避免环境触发,胰腺内分泌和外分泌功能不全的治疗,疼痛的管理,内镜或手术治疗以及胰腺癌的监测。笔者重点就PRSS1相关性遗传性胰腺炎的发病机制、治疗研究进展及疾病管理等方面进行综述。     

Chronic pancreatitis: relation to acute pancreatitis and pancreatic cancer

The relationship between chronic pancreatitis (CP) and other pancreatic diseases, such as acute pancreatitis (AP) and pancreatic cancer (PK), remains a fairly debated question. The progression from alcoholic AP to CP is controversial, and some long-term epidemiological studies suggest that alcoholic CP might be the result of recurrent alcoholic AP (necrosis-fibrosis sequence) and a subgroup of alcoholics may present recurrent AP without progression to CP. Other predisposing factors (genetic, nutritional, environmental) seems to be important in inducing different outcomes of pancreatic damage due to alcohol. However, recurrent episodes of AP are clearly involved in pathophysiology of CP in patients with hereditary pancreatitis. A relationship between CP and subsequent PK development has long been suspected, but we actually don't know whether this association is direct or is the result of confounding factors, such as alcohol intake or cigarette smoking. Many issues should be considered as indicators of a causal association, and several of them are not fulfilled. Nonetheless, epidemiological studies (case-control or cohort studies) showed that the risk of PK is increased in patients with CP; the risk is significantly higher in tropical calcifying CP and hereditary pancreatitis. Studies on growth factors, oncogenes, tumor-suppressor genes, and angiogenesis suggest that the sequence PC-KP is plausible from the biological standpoint.     

Pancreatitis and hyperparathyroidism

Hypercalcaemia is considered to be a rare cause of pancreatitis but the true cause-and-effect relationship between hyperparathyroidism and pancreatic inflammatory disease remains controversial. Over 100 patients have been reported in whom both processes have occurred concurrently, but doubts have been expressed as to whether or not this association is due to chance. We report 10 new cases of hypercalcaemic hyperparathyroidism associated with different types of pancreatitis. Seven patients had primary hyperparathyroidism and three had hyperparathyroidism after renal transplantation. Two experienced acute pancreatitis after parathyroidectomy. Of the remaining eight patients, five had hypercalcaemia equal to or above 120 mg/l. The prevalence of pancreatitis in our series of 86 cases of primary hyperparathyroidism is 8 per cent. Acute and chronic calcifying types of pancreatitis were observed. Three patients died of the disease, two of them after renal transplantation. It is suggested that pancreatitis may complicate the clinical course of hyperparathyroidism, particularly when hypercalcaemia is moderate to severe and/or there are other risk factors such as treatment with steroids and azathioprine after renal transplantation.     

Hereditary pancreatitis - a clinically relevant cause of pancreatic adenocarcinoma?]

Hereditary pancreatitis is an autosomal dominant disease. Recently, the genetic defect has been mapped to chromosome 7q35 and consists mainly of a point mutation in exon 3 of the cationic trypsinogen gene which causes an Arg(CGC)-His(CAC) substitution at residue 117. In patients with hereditary pancreatitis the estimated cumulative risk for pancreatic carcinoma to age 70 approaches 40 %. Thus, the role of hereditary pancreatitis in the pathogenesis of pancreatic carcinoma is of interest.PATIENTS AND METHODS: DNA was extracted from peripheral blood (n = 16), fresh tumor tissue (n = 29) and formalin fixed and paraffin embedded tumor tissue (n = 5) of 50 patients with ductal adenocarcinoma of the pancreas. We specifically amplified exon 3 and the intronic flanking sequences of the cationic trypsinogen gene by nested PCR and performed restriction fragment length polymorphism analysis using the restriction enzyme Afl III. In patients with hereditary pancreatitis the G : A point mutation creates a recognition site for Afl III which is not present in unaffected individuals.RESULTS: None of the 50 patients with ductal adenocarcinoma of the pancreas revealed the G : A point mutation in exon 3 of the cationic trypsinogen gene which is characteristic of hereditary pancreatitis. In addition sequencing of exon 3 did not reveal any other mutations in the DNA of patients with pancreatic adenocarcinoma.CONCLUSION: Although hereditary pancreatitis markedly increases the risk for pancreatic cancer, it is rare and probably of little significance with respect to the pathogenesis of the majority of pancreatic adenocarcinomas.     

Famili?res Pankreaskarzinom

Less than 10% of pancreatic ductal adenocarcinomas are based on a hereditary syndrome. In contrast a positive family history for pancreatic cancer raises the individual risk for the development of pancreatic and extrapancreatic malignancies. While 70% of hereditary pancreatic carcinomas can be attributed to the familiar pancreatic cancer syndrome 30% are caused by other hereditary syndromes, e.g., Peutz-Jeghers syndrome or familial adenomatous polyposis. Furthermore, genetically determined pancreatitis (e.g., hereditary pancreatitis or cystic fibrosis) can lead to pancreatic cancer. Up to now conclusive data for routine screening of high risk patients are not available which is due in part to the difficult identification of high risk patients and the problematic classification of detected pancreatic lesions. Therefore, high risk patients should be included in controlled clinical trials for screening. Small pancreatic lesions are not clear indications for surgical resection as false positive results can hamper a clear diagnosis and prophylactic pancreatectomy is not recommended. In the case of a histologically proven carcinoma a prophylactic extension of resection might be reasonable. Prevention of familial pancreatic cancer can be achieved through nicotine abstinence.     

Chronic pancreatitis

Chronic pancreatitis is distinguished by structural and functional criteria. Alcohol is the major aetiological factor, but other causes (for example including hereditary pancreatitis) must be considered. Abdominal pain is the usual presenting feature, but chronic pancreatitis is clinically silent in many patients. The pathogenesis of chronic pancreatitis is incompletely understood. Diagnosis is usually made on imaging (computed tomography, magnetic resonance cholangiopancreatography, endoscopic ultrasound). Complications include exocrine and endocrine insufficiency, obstructive jaundice, duodenal obstruction, left-sided portal hypertension, and the development of pancreatic cancer. Overall management is difficult and depends upon symptoms, morphological characteristics and complications. Treatment options include medical, endoscopic, and surgical strategies; the latter is reserved for patients with complications. Early involvement of a specialist centre in the care of patients with complicated chronic pancreatitis is important and should be encouraged.     

Somatostatin analogues in the prevention of pancreas-related complications after pancreatic resection

Background/Purpose The Achilles' heel of operative pancreatectomies is the pancreaticoenterostomy for proximal resections and the pancreatic parenchymal closure for distal resections. Inhibition of pancreatic exocrine secretions by somatostatin analogues has been suggested to decrease pancreas-specific complications, but this topic remains controversial. Methods We performed a randomized, prospective, placebo-controlled, multicenter trial of the use of perioperative vapreotide, a potent somatostatin analogue, in pancreatic resections for presumed neoplasms in 381 patients without chronic pancreatitis. We also reviewed the literature on the use of somatostatin and its analogues after pancreatectomy. Results When compared to the placebo, perioperative vapreotide had no effect on overall pancreas-specific complications (30.4% vs 26.4%), mortality (0% vs 1.4%), overall complications (40% vs 42%), and duration of hospitalization; there were no differences in complications per type of resection with use of vapreotide — proximal versus distal resection. Seven other prospective, randomized trials provide differing results. Conclusions Our study with vapreotide failed to show any benefit when administered perioperatively (and for 7 days postoperatively) on pancreas-specific complications after major pancreatectomy in patients without chronic pancreatitis. The use of perioperative analogues that suppress pancreatic exocrine secretion seems not to be warranted as routine treatment.     

Chronic pancreatitis

Chronic pancreatitis is distinguished by structural and functional criteria. Alcohol is the major aetiological factor, but about 20% of patients have another cause such as hereditary pancreatitis. Abdominal pain is the usual presenting feature, often as recurrent attacks of acute pancreatitis but chronic pancreatitis may be clinically silent. The pathogenesis of chronic pancreatitis is incompletely understood. Diagnosis is usually made on imaging (CT, magnetic resonance cholangiopancreatography – MRCP, endoscopic ultrasound). Complications include exocrine and endocrine insufficiency, obstructive jaundice, duodenal obstruction, left-sided portal hypertension, and the development of pancreatic cancer. Overall management is difficult and depends upon symptoms, morphological characteristics and complications. Treatment options include medical, endoscopic, and surgical strategies; the latter is reserved for patients with complications. Early involvement of a specialist centre in the care of patients with complicated chronic pancreatitis is important and should be encouraged.     

Chronic pancreatitis

Chronic pancreatitis is distinguished by structural and functional criteria. Alcohol is the major aetiological factor, but about 20% of patients have another cause such as hereditary pancreatitis. Abdominal pain is the usual presenting feature, often as recurrent attacks of acute pancreatitis but chronic pancreatitis may be clinically silent. The pathogenesis of chronic pancreatitis is incompletely understood. Diagnosis is usually made on imaging (CT, magnetic resonance cholangiopancreatography, endoscopic ultrasound). Complications include exocrine and endocrine insufficiency, obstructive jaundice, duodenal obstruction, left-sided portal hypertension, and the development of pancreatic cancer. Overall management is difficult and depends upon symptoms, morphological characteristics and complications. Treatment options include medical, endoscopic, and surgical strategies; the latter is reserved for patients with complications. Early involvement of a specialist centre in the care of patients with complicated chronic pancreatitis is important and should be encouraged.     

Complications after Frey's procedure for chronic pancreatitis

BACKGROUND: Frey's operation is indicated on patients with chronic pancreatitis who have "head dominant" disease and involves resection of the head of pancreas and lateral pancreaticojejunostomy (LRLPJ). There is little information about the postoperative complications after this procedure and the factors likely to be responsible for them. This paper addresses this aspect of LRLPJ. METHODS: A retrospective review was made of records of 41 patients undergoing LRLPJ for chronic pancreatitis between January 1990 to June 2003. RESULTS: Sixteen (39%) patients had 19 complications in the early postoperative period; septic complications were the commonest. One patient died. Regression analysis showed preoperative endoscopic pancreatic stenting to be the factor responsible for majority of these complications (P = 0.0041). Patients with a history of pancreatic stenting had a prolonged hospital stay (P = 0.022). CONCLUSIONS: Postoperative complications after LRLPJ are usually septic in nature and are likely to occur more often in patients in whom endoscopic pancreatic stenting has been performed before surgical intervention.     

Hereditary Pancreatitis: Endoscopic and Surgical Management

Introduction

Hereditary pancreatitis is a rare cause of chronic pancreatitis. In recent years, genetic mutations have been characterized. The rarity of this disorder has resulted in a gap in clinical knowledge. The aims were to characterize patients with hereditary pancreatitis and establish clinical guidelines.

Methods

Pediatric and adult endoscopic, surgical, radiologic, and genetic databases from 1998 to 2012 were searched. Patients with recurrent acute or chronic pancreatitis and genetic mutation for either PRSS-1, SPINK-1, or CFTR or those who met the family history criteria were included. Patients with pancreatitis due to other causes, without a positive family history, familial pancreatic cancer, or cystic fibrosis, were excluded.

Results

Eighty-seven patients were identified. Genetic testing confirmed the diagnosis in 54 patients (62 %). Eighty-five patients (98 %) underwent 263 endoscopic procedures including sphincterotomy (72 %), stone removal (49 %), and pancreatic duct stenting (82 %). Twenty-eight patients (32 %) have undergone 37 operations which included 19 resections and 18 drainage procedures. The interval between procedures for recurrent pain was longer for surgery than for endoscopic therapy (9.1 vs. 3.4 years, p?<?0.05).

Conclusions

Most children and young adults with hereditary pancreatitis can be managed initially with endoscopic therapy. When surgery is undertaken, the procedure should be tailored to the pancreatic anatomy and cancer risk.     

Serum ribonuclease elevations and pancreatic necrosis in acute pancreatitis.

Pancreatic necrosis is a principal determinant of the severity, duration, and infectious complications of acute pancreatitis. There has been no objective index for pancreatic necrosis, and its recognition has necessarily rested upon nonspecific clinical signs, including later deterioration or appearance of sepsis. In search of such an index, we have measured serum levels of a poly-[C]-specific acid ribonuclease (RNase) in 38 patients with acute pancreatitis, 12 patients with chronic pancreatitis, and 50 control patients. The values in chronic pancreatitis (mean, 52 units; range, 33 to 80 units) were within observed normal limits (mean, 51; range, 17 to 94). The values in acute pancreatitis segregated into two groups, normal values (group A) and high values (group B). Of 25 patients in group A (mean, 46; range, 19 to 87), only one developed evidence of pancreatic necrosis or abscess. In contrast, of the 13 patients in group B (mean, 192, range, 98 to 385), 11 required surgical debridement/drainage for pancreatic necrosis (six) or abscess (five) (P less than 0.001). Each of the other two patients had prolonged pancreatic inflammation with fever and a pancreatic mass which persisted for more than 2 weeks. RNase levels in group B patients rose within a few days after onset of pancreatitis and tended to parallel the clinical course. These findings suggest that measurement of serum RNase in acute pancreatitis gives a reliable indication of pancreatic necrosis. Therefore RNase determinations should be of value for earlier identification and monitoring of patients at high risk of late complications, and for helping to select those who will benefit from early debridement before secondary infection occurs.     

Chronische Pankreatitis

Chronic pancreatitis is characterized by periodic episodes of inflammation and loss of exocrine and endocrine function of the pancreas. Hereditary pancreatitis is an autosomal dominant disorder with an 80% penetrance, is associated with recurrent episodes of pancreatitis starting in early childhood and correlated to an increased risk of pancreatic cancer. The pathogenesis of chronic and hereditary pancreatitis is not yet fully understood. Patients suffering from chronic pancreatitis present with belt-like abdominal pain, weight loss, and often diabetes mellitus. The diagnosis is made by a combination of imaging procedures such as ultrasound and endoscopic retrograde cholangiopancreatography and exocrine and endocrine function tests. Therapy is restricted to symptom control. Approximately 30–60% of all patients develop disease-associated complications such as persistent pain, strictures of the common bile duct, or pancreatic duct stones which require either interventional or surgical treatment.     

Hereditary pancreatitis and mutations of the cationic trypsinogen gene

BACKGROUND: Mutations of the cationic trypsinogen gene have been detected in hereditary pancreatitis. This article reviews current understanding of their function and clinical significance. METHODS: An unrestricted Medline search was conducted using the key words hereditary pancreatitis and 'cationic trypsinogen . Additional material was obtained from references cited in original papers and recently published abstracts of meetings. RESULTS AND CONCLUSION: Cationic trypsinogen mutations have been identified in most, but not all, families with hereditary pancreatitis. This confirms existing evidence that premature trypsinogen activation plays a central role in the pathogenesis of human pancreatitis. Patients currently clinically defined as having hereditary pancreatitis should be screened for the presence of cationic trypsinogen mutations. A subgroup of patients with non-hereditary pancreatitis may also benefit from being screened for these mutations. Patients with hereditary pancreatitis should be entered into prospective, multicentre trials investigating secondary screening for pancreatic cancer. Gene therapy for hereditary pancreatitis is beyond current technological capability but remains a future therapeutic prospect for this often debilitating condition.     

Chronic pancreatitis. Diagnosis and treatment]

Chronic pancreatitis is characterized by periodic episodes of inflammation and loss of exocrine and endocrine function of the pancreas. Hereditary pancreatitis is an autosomal dominant disorder with an 80% penetrance, is associated with recurrent episodes of pancreatitis starting in early childhood and correlated to an increased risk of pancreatic cancer. The pathogenesis of chronic and hereditary pancreatitis is not yet fully understood. Patients suffering from chronic pancreatitis present with belt-like abdominal pain, weight loss, and often diabetes mellitus. The diagnosis is made by a combination of imaging procedures such as ultrasound and endoscopic retrograde cholangiopancreatography and exocrine and endocrine function tests. Therapy is restricted to symptom control. Approximately 30-60% of all patients develop disease-associated complications such as persistent pain, strictures of the common bile duct, or pancreatic duct stones which require either interventional or surgical treatment.     

Hereditary pancreatitis in children: surgical implications with special regard to genetic background

Purpose

Hereditary pancreatitis (HP) is the primary etiology of chronic pancreatitis during childhood, progressing through recurrent episodes of acute pancreatitis and finally leading to pancreatic insufficiencies. Hereditary pancreatitis is because of mutations of the cationic trypsinogen (PRSS1) gene. Some other genes, such as SPINK1 or CFTR, have been associated with familial idiopathic chronic pancreatitis. The aim of our study was to clearly define diagnostic and therapeutic strategies for HP patients, through an analysis of our study group and a review of the literature.

Methods

All children admitted from 1995 to 2007 with a final diagnosis of hereditary pancreatitis were restrospectively included in the study. We analyzed all medical records with special attention given to cases involving genetic screening (PRSS1, SPINK1, and CFTR genes).

Results

Ten children were included. Eight had HP with PRSS1 mutation, 2 of them without a familial history of chronic pancreatitis. The 2 others patients had SPINK1 mutations. Three HP patients were operated on for acute complications of pancreatitis and are well with a mean follow-up of 5.5 years. No patient had pancreatic insufficiencies or weight loss.

Conclusions

Hereditary pancreatitis is associated with severe pancreatitis, with a greater risk of developing pancreatic cancer. It must therefore be diagnosed correctly and treated to prevent its considerable complications.     

JPN Guidelines for the management of acute pancreatitis: epidemiology, etiology, natural history, and outcome predictors in acute pancreatitis

Acute pancreatitis is a common disease with an annual incidence of between 5 and 80 people per 100 000 of the population. The two major etiological factors responsible for acute pancreatitis are alcohol and cholelithiasis (gallstones). The proportion of patients with pancreatitis caused by alcohol or gallstones varies markedly in different countries and regions. The incidence of acute alcoholic pancreatitis is considered to be associated with high alcohol consumption. Although the incidence of alcoholic pancreatitis is much higher in men than in women, there is no difference in sexes in the risk involved after adjusting for alcohol intake. Other risk factors include endoscopic retrograde cholangiopancreatography, surgery, therapeutic drugs, HIV infection, hyperlipidemia, and biliary tract anomalies. Idiopathic acute pancreatitis is defined as acute pancreatitis in which the etiological factor cannot be specified. However, several studies have suggested that this entity includes cases caused by other specific disorders such as microlithiasis. Acute pancreatitis is a potentially fatal disease with an overall mortality of 2.1%–7.8%. The outcome of acute pancreatitis is determined by two factors that reflect the severity of the illness: organ failure and pancreatic necrosis. About half of the deaths in patients with acute pancreatitis occur within the first 1–2 weeks and are mainly attributable to multiple organ dysfunction syndrome (MODS). Depending on patient selection, necrotizing pancreatitis develops in approximately 10%–20% of patients and the mortality is high, ranging from 14% to 25% of these patients. Infected pancreatic necrosis develops in 30%–40% of patients with necrotizing pancreatitis and the incidence of MODS in such patients is high. The recurrence rate of acute pancreatitis is relatively high: almost half the patients with acute alcoholic pancreatitis experience a recurrence. When the gallstones are not treated, the risk of recurrence in gallstone pancreatitis ranges from 32% to 61%. After recovering from acute pancreatitis, about one-third to one-half of acute pancreatitis patients develop functional disorders, such as diabetes mellitus and fatty stool; the incidence of chronic pancreatitis after acute pancreatitis ranges from 3% to 13%. Nevertheless, many reports have shown that most patients who recover from acute pancreatitis regain good general health and return to their usual daily routine. Some authors have emphasized that endocrine function disorders are a common complication after severe acute pancreatitis has been treated by pancreatic resection.     

Pancreatic excisions for chronic pancreatitis and cancer: their rationale for "factual" surgery. Evidence-based medicine

Despite significant improvement in the results of pancreatoduodenecomy over recent years, the Whipple procedure and its main modifications still has a poor reputation. Based on the principles of evidence-based medicine, we reviewed the current status of pancreatoduodenectomy for pancreatic cancer and chronic pancreatitis. Mortality of pancreatoduodenectomy has declined to less than 5% for chronic pancreatitis and to 3-5% for pancreatic cancer. In contrast, overall morbidity remains high, ranging from 20% to 70%. Delayed gastric emptying accounts for almost 50% of all complications. Major relief of pain is achieved in 70% to 100% of patients with chronic pancreatitis. Overall 5-year survival for patients with pancreatic cancer remains poor, ranging from 5% to 15%, with a median survival of 13 to 17 months. Mortality ad morbidity are not related to the type of pancreatoduodenectomy, however patients with pancreatic cancer tend to have a higher risk for complications. Extended lymph node dissection and portal vein resection can be performed with similar mortality and morbidity compared with standard procedures, however without any survival benefit in the long-term course.     

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??Diagnosis treatment of chronic pancreatitis combinded with pancreatic duct stones MIAO Yi,JIANG Kui-rong. Department of Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
Corresponding author:MIAO Yi,E-mail: miaoyi@njmu.edu.cn
Abstract Chronic pancreatitis is a progressive fibroinflammatory disease with sustained damage of structure and function of pancreatic tissue, which results from a complex mix of causes (eg, alcohol, Biliary diseases), and often exists with intraductal calculi. Pain in the form of recurrent attacks of pancreatitis or constant and disabling pain is usually the main symptom. Steatorrhoea, diabetes, local complications associated with the disease are additional therapeutic challenges. Combined with a variety of imaging methods such as BUS, CT, ERCP and MRCP, etc. can significantly improve the diagnosis of chronic pancreatitis with pancreatic duct stone. Chronic pancreatitis with pancreatic duct stones should be actively treated, of which the focus is to control symptoms, improve function and treatment of complications with individual therapy. The appropriate surgery should be performed as soon as possible according to distribution of stone when the stone removal is not complete or recrudescent after extracorporeal shock wave lithotripsy and endoscopic. completely removing the lesion, taking out all the stones, removing the pancreas and bile duct obstruction, fully drainage of pancreatic juice and trying to save the pancreatic tissues are the goal of the surgery, which can significantly improve quality of life of patients.     

Surgical treatment of chronic pancreatitis

The results of surgery for chronic pancreatitis in fifty-seven patients treated between 1958 and 1972 were reviewed. The findings have been used to outline a surgical strategy for the management of this disease.Operations on the biliary tract gave disappointing results. Biliary disease must be treated when present, but this will not always lessen chronic pancreatic pain.The surgical treatment of pseudocysts by internal drainage was uncomplicated in the short run, but almost half the patients continued to have pain months or years later.Direct operations on the pancreas are most successful in chronic pancreatitis. Sphincterotomy, splanchnicectomy, gastric operations, and caudal pancreaticojejunostomy are no longer recommended. When the pancreatic duct is dilated, longitudinal pancreaticojejunostomy (Puestow operation) will effect improvement in 80 to 90 per cent of patients. Pancreatitis localized to the tail of the gland is optimally treated by hemipancreatectomy. Subtotal (95 per cent) pancreatectomy is reserved for diffuse pancreatitis when the pancreatic duct is small or when previous longitudinal pancreaticojejunostomy is unsuccessful.