Mutations of the cationic trypsinogen gene in patients with hereditary pancreatitis

BACKGROUND: Hereditary pancreatitis has been shown to be caused by one of two mutations (R117H and N21I) of the cationic trypsinogen gene (PRSS1). Families with hereditary pancreatitis in the north of England were investigated for these mutations. The clinical features associated with each mutation were compared. METHODS: In individuals from nine families with hereditary pancreatitis, DNA was screened for the R117H and N21I mutations. All five exons of the cationic trypsinogen gene were also sequenced to search for additional mutations. Haplotype analysis was carried out to identify common ancestors. Clinical data were collected. RESULTS: The R117H mutation was identified in three families and N21I in a further five. The R117H mutation was associated with a more severe phenotype than N21I in terms of mean(s.d.) age of onset of symptoms (8.4(7.2) versus 16. 5(7.1) years; P = 0.007) and requirement for surgical intervention (eight of 12 versus four of 17 patients respectively; P = 0.029). Haplotype analysis suggested that each mutation had arisen more than once. CONCLUSION: Two mutations in the cationic trypsinogen gene cause hereditary pancreatitis in eight of nine families originating in this region. The R117H mutation is associated with a more severe form of the disease in terms of age at onset of symptoms and requirement for surgical intervention.     

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.     

遗传性胰腺炎的基础研究与临床诊治进展

目的：探讨遗传性胰腺炎的基础研究及其诊断与治疗进展。方法：对近年的有关文献进行综述。结果：遗传性胰腺炎是胰腺炎的一种罕见类型，是一种有80％外显率的常染色体显性遗传病，其发病被认为是阳离子胰蛋白酶原基因突变所致，此类患者是胰腺癌的高发人群。结论：有关遗传性胰腺炎的研究取得了进展，这些研究为认识遗传性胰腺炎这一医学难题提供了许多有益的启示。     

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。     

Hereditary chronic pancreatitis: implications for surgical treatment and follow-up

Hereditary pancreatitis is an uncommon cause of chronic pancreatitis in Western society. It should be suspected when chronic pancreatitis presents in young adults. The diagnosis is made when chronic pancreatitis is present in several members of the same family who are determined not to have other risk factors for chronic pancreatitis. Molecular research focusing on mutations in the trypsinogen gene has uncovered the genetic defects associated with hereditary pancreatitis, and this knowledge has suggested the possible pathophysiologic mechanism of this disease. Because patients with hereditary pancreatitis develop their disease early in life they are very likely to require treatment for complications. As in patients with chronic pancreatitis of other etiologies those with hereditary pancreatitis should be treated medically for acute exacerbations. When complications occur or when the disease causes intractable pain surgery is recommended. Surgical therapy is tailored to the patient's pancreatic anatomy based on endoscopic retrograde cholangiopancreatography or CT scan. The two patients described in this report underwent successful longitudinal pancreaticojejunostomy (Puestow procedure) with good results. Finally it has been shown that patients with hereditary pancreatitis are at increased risk for developing pancreatic adenocarcinoma. Although not widely used pancreatic cancer screening programs have been suggested for surveillance of these patients.     

Detection of postoperative pancreatitis after pancreatic surgery by urine trypsinogen strip test

BACKGROUND: The urine trypsinogen strip test has been used successfully in the diagnosis of pancreatitis of various aetiologies, but has not been studied in postoperative pancreatitis. The aim of this study was to evaluate this test for the diagnosis of postoperative pancreatitis after pancreatic resection. METHODS: Fifty patients undergoing pancreatic resection were included. The urine trypsinogen strip test was done daily during the first postoperative week, blood was analysed before and 4, 6 and 10 days after surgery, and amylase activity in the drainage fluid was measured on days 4 and 6. Patients underwent computed tomography (CT) before operation and on days 2 and 6 afterwards. RESULTS: Thirteen patients (26 per cent) developed CT-detected pancreatitis after operation. In 12 of these patients pancreatitis was detected on the second postoperative day. The urine trypsinogen test was positive in all 13 patients with postoperative pancreatitis, and was already positive on the first day after surgery in 12. The sensitivity, specificity, and positive and negative predictive values of the trypsinogen strip test in detection of postoperative pancreatitis were 100, 92, 81 and 100 per cent respectively. In receiver-operator characteristic analysis the area under the curve (AUC) was higher for the urine trypsinogen strip test (AUC 0.959) than for a serum amylase level more than two (AUC 0.731) or three times (AUC 0.654) above the upper normal range in the diagnosis of postoperative pancreatitis. Patients whose recovery was complicated by pancreatic fistula, detected by drain output measurements on day 6, more often had a positive urine trypsinogen test than patients without a fistula (11 of 12 versus five of 38; P < 0.001). CONCLUSION: This study suggests that the urine trypsinogen strip test might be a valuable method for diagnosis of pancreatitis after pancreatic surgery.     

Clinical evidence of pathogenesis in chronic pancreatitis

Chronic pancreatitis is a continuing inflammatory disease characterized by irreversible morphological change and, typically, by pain and permanent impairment of function. The pathogenesis of pancreatitis, either acute or chronic, is still controversial. There have been no widely accepted concepts to provide a reasonable explanation linking the known etiological factors and the pathophysiological aspects of the disease. Alcohol is undoubtedly the major etiological factor in most countries, and the relative importance of alcohol as a cause of chronic pancreatitis ranges from 40% to 90% in various countries. As fewer than 10% of alcoholics develop chronic pancreatitis, other nutritional or genetic influences are likely to be involved in the pathogenesis of alcoholic pancreatitis. Accessory pancreas incidentally found in patients with chronic alcoholic pancreatitis does not always have the pathological findings seen in the main pancreas. Integrity of the pancreatic duct seems to be another important factor for chronic alcoholic pancreatitis. Gene mutations of the cystic fibrosis transmembrane conductance regulator (CFTR), cationic trypsinogen, and pancreatic secretory trypsin inhibitor have been investigated in idiopathic chronic pancreatitis. Molecular and cell biology research during the past few years has elucidated pathophysiological factors that are involved in the pathogenesis of chronic pancreatitis, but cannot demonstrate a common pathway between etiological factors and the pathogenesis or development of the disease. Received: March 20, 2002 / Accepted: April 15, 2002 Offprint requests to: T. Hayakawa     

Hereditary pancreatitis caused by a new mutation in the trypsinogen gene. Report of a family

Hereditary pancreatitis is an uncommon autosomal dominant disease secondary to a mutation normally located in the trypsinogen gene, preventing trypsin deactivation. This mutation translates clinically into recurrent attacks of acute pancreatitis and an increased risk of pancreatic cancer. We report a case of acute hereditary pancreatitis due to a trypsinogen mutation that has previously been described in only one family.     

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.     

Genetics of pancreatitis.

There was some recent progress in the understanding of genetic risk factors in chronic pancreatitis. Due to this progress some of the traditional views of the subject will change. Today, genetic risk factors are attributed a much more important role that in the past. The frequency and strength of mutations were higher than expected. Strong variants were the rare autosomal-dominant mutations N29I and R122H of PRSS1 (cationic trypsinogen) and homozygous N34S of SPINK1 (pancreatic secretory trypsin inhibitor). Other mutations (heterozygous N34S, CFTR) were of lower relevance but still mediate a higher risk than alcohol consumption. The course of genetically determined pancreatitis is rather mild. In the long term pancreas cancer was found in some patients but apart from non-smoking no adequate prophylactic strategy is available up to now.     

Preventive gastrectomy in patients with gastric cancer risk due to genetic alterations of the E-cadherin gene defect

BACKGROUND: Germline mutations in the E-cadherin gene CDH1 have recently been described that seem to be responsible for the development of hereditary diffuse gastric cancer. METHODS: The world literature on familial gastric cancer is reviewed in terms of mutations of the E-cadherin gene CDH1. RESULTS: There are reports of 18 families worldwide with hereditary diffuse gastric cancer due to germline mutations of the E-cadherin gene CDH1. Germline mutations of the E-cadherin gene CDH1 lead to hereditary diffuse gastric cancer with a penetrance of about 70%. An early onset with an average age of 38 years in men and women is typical for this autosomal dominant inherited disease. Until now preventive total gastrectomies with hereditary diffuse gastric cancer have been reported in five patients. CONCLUSIONS: Preventive total gastrectomy should be the procedure of choice in patients with a germline mutation of the E-cadherin gene CDH1. Patients with a genetic risk for familial gastric cancer who reject preventive total gastrectomy must be followed-up intensively by endoscopy every 6-12 months.     

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.     

Activation peptide of carboxypeptidase B and anionic trypsinogen as early predictors of the severity of acute pancreatitis

BACKGROUND: Early prediction of severity is important in the management of patients with acute pancreatitis. The presence of activation peptides and certain pancreatic proenzymes in plasma and urine has been shown to correlate with severity. This study was designed to assess the value of measuring levels of the activation peptide of carboxypeptidase B (CAPAP) and of anionic trypsinogen. METHODS: Concentrations of CAPAP and anionic trypsinogen were measured in the urine and serum in 60 patients with acute pancreatitis. Preset cut-off levels were used to analyse the accuracy of the tests. Severity was classified retrospectively according to the Atlanta classification. RESULTS: Concentrations of CAPAP in urine and serum and of anionic trypsinogen in urine correlated with the severity of the pancreatitis. CAPAP in urine showed the highest accuracy. The overall accuracy was 90 per cent, with a positive predictive value of 69 per cent and a negative predictive value of 98 per cent. CONCLUSION: In this study, measurement of CAPAP in urine was an accurate way to predict the severity of acute pancreatitis, and was superior to assay of anionic trypsinogen in urine and serum. Measurement of CAPAP in urine may be of value in the management of individual patients with pancreatitis and in the selection of patients for therapeutic trials.     

Role of the protease-antiprotease balance in peritoneal exudate during acute pancreatitis.

The peritoneal exudate formed during experimental pancreatitis is toxic when administered intraperitoneally or intravenously to other animals. Overwhelming of the peritoneal antiprotease defences by proteolytic enzymes released from the pancreas may be a key factor responsible for this toxicity and is examined in the current study. Human pancreatitis exudates possessed tryptic amidase activity indicating trypsinogen activation. The trypsin inhibitory capacities of exudates were reduced indicating a degree of consumption of the peritoneal antiproteases. Of 21 exudates examined, three showed marked reduction of their trypsin inhibitory capacity indicating almost complete consumption of their antiproteases. All three patients were shocked at the time of sampling, two dying of fulminant pancreatitis within 24 h. Overwhelming of the peritoneal antiproteases was not confirmed, but may occur in a few instances where proteolytic enzyme release or zymogen activation continues. Intraperitoneal administration of exogenous antiproteases prolongs survival in rats with pancreatitis and has been suggested as a therapy in man. The current data suggests that few patients are likely to benefit from such an approach.     

Surgical management of recurrent pancreatitis in children with pancreas divisum

OBJECTIVE: To analyze an institutional experience with pancreatitis in childhood to clarify the frequency of pancreas divisum in that patient population, the characteristics of pancreatitis in children with pancreas divisum, and the role of surgical management in their treatment. SUMMARY BACKGROUND DATA: The role of pancreas divisum in causing acute and relapsing pancreatitis and chronic, recurring abdominal pain is controversial. Although the anatomical abnormality is present from birth, most investigators have reported cases with onset of symptoms in adulthood. The reported pediatric experience with this disorder is small, and the natural history of pancreatitis in children with pancreas divisum has not been well elucidated. METHODS: A retrospective chart review of all children 18 years of age and younger with a discharge diagnosis of pancreatitis identified 135 patients treated in the authors' institution from 1978 to 1998. Ten patients were found to have anatomical variants of pancreas divisum associated with recurrent or chronic pancreatitis. The medical records of these patients were reviewed for data on the presentation, diagnostic findings, imaging studies, treatment, surgical findings, and pathologic findings in these children. Chart review and telephone calls were used to assess the current state of health in nine patients available for follow-up. RESULTS: Pancreas divisum was identified in 7.4% of all children with pancreatitis and 19.2% of children with relapsing or chronic pancreatitis. Patients had early onset of recurrent episodic epigastric pain and vomiting, at a mean age of 6 years. Three patients had a positive family history of pancreatitis and one was proven by DNA analysis to have hereditary pancreatitis. Pancreatitis was documented by elevated amylase or lipase levels, and endoscopic retrograde cholangiopancreatography was the method of diagnosis of pancreas divisum in all patients. Eight patients had complete pancreas divisum and two had incomplete variants. Eight patients underwent surgery to improve ductal drainage. Seven underwent transduodenal sphincteroplasty of the accessory papilla, along with sphincteroplasty of the major papilla in two (plus septoplasty in one). Three patients underwent longitudinal pancreaticojejunostomy, as a primary procedure in one patient with midductal stenosis and in two because of recurring pancreatitis after sphincteroplasty. The surgical findings and histologic examination of five patients undergoing distal pancreatectomy revealed striking changes of advanced chronic pancreatitis. Patients responding to sphincteroplasty alone showed less severe histologic changes. Overall, three of seven patients had excellent results, three were improved, and one had continued disabling attacks of pancreatitis. The mean duration of follow-up was 7.3 years, and there were no deaths. No patients had endocrine or exocrine pancreatic insufficiency, and none required chronic analgesics. CONCLUSIONS: Pancreas divisum is an important cause of recurrent pancreatitis in childhood and should be sought aggressively in children with more than one episode of pancreatitis or pancreatitis with a history of chronic recurrent abdominal pain. Surgical intervention is directed toward relief of ductal obstruction and may involve accessory duct sphincteroplasty alone or in combination with major sphincteroplasty and septoplasty. Patients with more distal ductal obstruction or ductal ectasia may benefit from pancreaticojejunostomy.     

Current standards of surgery for pancreatic cancer

BACKGROUND: Pancreatic cancer carries a dismal prognosis but there has been a vast increase in evidence on its management in the past decade. METHODS: An electronic and manual search was performed for articles on the surgical treatment of pancreatic cancer published in the past 10 years. RESULTS: Six major areas of advancement were identified. Groups at high risk of developing pancreatic cancer, notably those with chronic pancreatitis and hereditary pancreatitis, have been defined, raising the need for secondary screening. Methods of staging pancreatic cancer for resection have greatly improved but accuracy is still only 85-90 per cent. Pylorus-preserving partial pancreatoduodenectomy without extended lymphadenectomy is the simplest procedure; it does not compromise long-term survival. Adjuvant chemotherapy significantly improves long-term survival. Patients who are free from major co-morbidity have better palliation by surgery (with a double bypass) than by endoscopy. High-volume centres improve the results of surgery for all outcome measures including long-term survival. CONCLUSION: The surgical management of pancreatic cancer has undergone a significant change in the past decade. It has moved away from no active treatment. The standard of care can now be defined as potentially curative resection in a specialist centre followed by adjuvant systemic chemotherapy.     

What's new in the management of acute pancreatitis?

Acute severe pancreatitis remains a disease with multiple complications and high mortality rates. The body of knowledge about clinical pancreatitis is being subjected to rigorous evidence-based analysis, and relevant, practical guidelines have been issued. Great efforts are being made to identify and profile the mediators involved in the systemic hyperinflammatory response to acute pancreatic injury. Lexipafant, a platelet-activating factor antagonist that showed promising results in initial trials, failed to reduce the incidence of new organ failures or mortality in a large double-blind study. The search for an early and accurate prognostic marker for severity persists, with urinary trypsinogen activation peptide as a potentially suitable candidate. Patients with acute pancreatitis do not benefit from anti-secretory therapy with octreotide. Percutaneous, radiological, drainage techniques may eventually play an important role in the management of infected necrosis.     

Characterization of immunoreactive trypsin as a means of differentiating graft pancreatitis and allograft rejection after porcine pancreatic transplantation.

Graft pancreatitis and allograft rejection were both accompanied by increased serum levels of immunoreactive anionic trypsin (irAT) in a porcine pancreatic allograft transplantation model. Characterization of this immunoreactivity by gel filtration revealed different elution profiles in these conditions that can be helpful in the differentiation between them. During graft pancreatitis, a major part of the immunoreactivity was found within the high-molecular-weight fraction corresponding to the formation of complexes between trypsin and protease inhibitors. During allograft rejection, virtually all serum irAT increase could be attributed to the release of anionic trypsinogen without any evidence of activation. Since this transplantation model includes urinary diversion of the exocrine secretions, irAT and immunoreactive cationic trypsin (irCT) can also be measured in the urine. Characterization of this immunoreactivity showed that most of both irAT and irCT was found as active trypsin but a minor part was probably complexed with some protease inhibitor (possibly pancreatic secretory trypsin inhibitor [PSTI]).     

Acute pancreatitis induced by ifosfamide therapy

Ifosfamide used in the treatment of pediatric solid tumors is known to have serious adverse effects, including acute pancreatitis, a rare complication of therapy. This report describes a young girl who developed acute pancreatitis while being treated for recurrent Wilms tumor with the ifosfamide, carboplatin, and etoposide regimen. She recovered completely and without sequelae from ifosfamide-induced pancreatitis soon after the drug was stopped. Abdominal pain in patients on anticancer treatment is a common occurrence, but it is rarely investigated. Patients who receive ifosfamide as part of a chemotherapy regimen should be carefully monitored, and symptoms or signs suggestive of acute pancreatitis should be promptly investigated. Withholding the drug usually leads to complete recovery.