Pancreatic Cancer Following Acute Pancreatitis: A Population-based Matched Cohort Study
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Abstract:
BACKGROUND: Acute pancreatitis is linked to pancreatic cancer, but the direction of this association is not fully elaborated. METHODS: This was a population-based cohort study including all Swedish residents diagnosed with a first-time episode of acute pancreatitis between 1997 and 2013 and corresponding matched pancreatitis-free individuals from the general population. Hazard ratios for the association between acute pancreatitis and pancreatic cancer were estimated using multivariable Cox regression models. RESULTS: Overall, 49,749 individuals with acute pancreatitis and 138,750 matched individuals without acute pancreatitis were followed up for 1,192,134 person-years (median 5.3 years). A total of 769 individuals developed pancreatic cancer, of whom 536 (69.7%) had a history of acute pancreatitis. The risk of pancreatic cancer was substantially increased during the first few years after a diagnosis of acute pancreatitis but declined gradually over time, reaching a level comparable to the pancreatitis-free population after >10 years of follow-up. In those with non-gallstone-related acute pancreatitis, the risk of pancreatic cancer declined to a level comparable to the pancreatitis-free population only when follow-up time was censored for a second episode of acute pancreatitis or a diagnosis of chronic pancreatitis. Increasing number of recurrent episodes of acute pancreatitis was associated with increased risk of pancreatic cancer. CONCLUSION: These findings imply a delay in the diagnosis of pre-existing pancreatic cancer, if clinically presented as acute pancreatitis. Any association between non-gallstone-related acute pancreatitis and pancreatic cancer in the long-term (>10 years) could be mediated through recurrent acute pancreatitis or chronic pancreatitis.Keywords:
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Hereditary pancreatitis is a rare form of chronic recurrent pancreatitis. A family, in which 11 members had chronic pancreatitis, five had diabetes, and two had pancreatic cancer, was studied, and hereditary pancreatitis was diagnosed in all patients by demonstrating the mutation in exon 3 of the cationic trypsinogen gene (R117H). The clinical implications of genotypic analysis in hereditary pancreatitis are discussed.
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Several studies have reported an increased frequency of cystic fibrosis gene mutations in idiopathic but not in alcoholic chronic pancreatitis. The impact of cystic fibrosis gene mutations on the long-term course of chronic pancreatitis has not been analyzed. The aim of our study was to determine the frequency of cystic fibrosis gene mutations in patients with chronic pancreatitis with long-term follow-up and to see whether patients with mutations have a clinically different natural course compared to those without mutations.Eighty two patients with chronic pancreatitis and 11 patients with recurrent acute pancreatitis of our well defined pancreatitis cohort were screened for the 31 most common cystic fibrosis gene mutations. The impact of cystic fibrosis gene mutations on the long-term course of chronic pancreatitis was assessed.A cystic fibrosis gene mutation was detected in five of 49 patients with alcoholic chronic pancreatitis (10.2%; 2.3 times the expected frequency) and in three of 14 patients with idiopathic-juvenile chronic pancreatitis (21.4%; 4.8 times the expected frequency). No mutations were found in the remaining patients with chronic pancreatitis of rare causes, hereditary pancreatitis, and recurrent acute pancreatitis. The frequency of pancreatic calcifications was significantly higher in patients with alcoholic chronic pancreatitis without mutations. This result was not confirmed in patients with idiopathic-juvenile chronic pancreatitis. The duration of pain and the frequency of exocrine and endocrine insufficiency was comparable in both subgroups irrespective of the mutation status.Our data indicate a significantly increased frequency of cystic fibrosis gene mutations both in patients with alcoholic and idiopathic-juvenile chronic pancreatitis. The natural course was similar in patients with mutations compared to those without mutations.
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Since the discovery of the cationic trypsinogen gene mutations in patients with hereditary pancreatitis, a variety of pancreatitis-associated gene mutations have been reported, including pancreatic secretory trypsin inhibitor and cystic fibrosis transmembrane conductance regulator. Although the patients with these mutations are rarely seen, genetic disorders inducing pancreatitis have provided us major breakthroughs to understand the molecular basis of the disease. Furthermore, the major stream in pancreatology has been evidenced in patients with hereditary pancreatitis: acute pancreatitis --> chronic pancreatitis --> pancreatic cancer. This report will focus on the pancreatitis-associated genes and the molecular mechanism of pancreatitis associating with these gene mutations.
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Introduction: Patients with Cystic fibrosis (CF) are prone to multiple pancreatic complications including pancreatic insufficiency, pancreatitis, and diabetes. Pancreatic insufficiency is typically associated with more severe CF mutations, while pancreatitis is felt to be more common with milder mutations. The goal of this study was to examine the impact of various CF mutations on pancreatitis in one of the nation’s largest adult CF programs. Methods: We identified patients with CF and pancreatitis at a large, tertiary referral center using ICD-9, ICD-10, and SNOMED codes. All CF patients meeting inclusion criteria were reviewed to identify their specific genetic mutations. The frequencies of pancreatic manifestations were examined in the large adult CF cohort. The types of genetic mutations were examined in groups of CF patients with and without pancreatitis. Results: In the cohort of adult CF patients, 45.1% had pancreatic insufficiency, 24.2% had CF-related diabetes, and 16.2% had experienced pancreatitis. There was a significant difference in the number of mutations identified in CF patients with and without pancreatitis (p=0.008). In both pancreatitis and non-pancreatitis CF patients, the vast majority had two identified mutations (87.7% and 89.7%, respectively). 9.2% of those with pancreatitis had only one mutation, and 10.1% of those without pancreatitis had only one mutation as well. However, we observed a significantly greater amount of pancreatitis patients with three mutations than expected, while there were fewer than expected non-pancreatitis patients with three mutations (3.1% and 0%, respectively). The groups’ distributions of mutation classes were also significantly different (p<0.0001). More patients with pancreatitis had the combination of one CF and one VVCC mutation than predicted. Conversely, more non-pancreatitis patients carried two CF mutations than predicted. Overall, variants of varying clinical consequence (VVCC) were much more common in the group with pancreatitis (35.4%) relative to those without pancreatitis (6.1%). Conclusion: In a large adult CF cohort, pancreatitis was a very common manifestation, seen in 16.2% of patients. Variants of varying clinical consequence were much more common in the group with pancreatitis than in those without. Whether CFTR modulators can impact recurrent pancreatitis in patients with one mutation or in patients with less severe mutations is an important potential area for further investigation.
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Fifteen years ago the discovery of a mutation of the cationic trypsinogen gene (PRSS1) in patients with hereditary chronic pancreatitis supported Hans Chiari’s theory that chronic pancreatitis is the result of autodigestion of the pancreas and depicted the fundament for further research in this field. A genetic basis for chronic pancreatitis had to be assumed in a pedigree described by Comfort and Steinberg already in 1952 it needed additional 44 years to identify this first genetic association. Thereafter, research had its focus on proteases and anti-proteases that are assembled in the digestive enzyme cascade, an approach that identified serine protease inhibitor, Kazal type 1 (SPINK1) as another pancreatitis gene. Aside the digestive enzyme cascade, the cystic fibrosis transmembrane conductance regulator gene (CFTR) that is responsible for Cystic Fibrosis, was investigated by two groups and both found an enrichment of CFTR variants in patients with chronic pancreatitis. Support for this investigation came from Cystic Fibrosis, where 1-2% of patients suffer from chronic pancreatitis. New aspects in the field of genetics in chronic pancreatitis emerged in the last five years. A variant of anionic trypsinogen (PRSS2) was found to be overrepresented in controls and protects against chronic pancreatitis. Additionally, variants of the calcium sensing receptor (CASR) seem to influence the pathogenesis of chronic pancreatitis in SPINK1 p.N34S carriers. Triplication and duplication of the trypsinogen locus represents a completely new disease causing mechanism that predisposes to chronic pancreatitis by a so-called gene dosage effect. Identification of chymotrypsin C (CTRC) as the enigmatic Enzyme Y described by Rinderknecht over 20 years ago displayed another reasonable candidate gene. Investigations of CTRC found low penetrance loss of function variants that diminish secretion and/or activity of CTRC and thereby contribute to the development of the disease. Taken together recent data further support the importance of a balanced digestive enzyme cascade in that trypsin captures a key role. Further research in this field will yield additional associated genes by hypothesis-driven and hypothesis free approaches.
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Hereditary pancreatitis is an autosomal dominant condition, which results in recurrent attacks of acute pancreatitis, progressing to chronic pancreatitis often at a young age.The majority of patients with hereditary pancreatitis express one of two mutations (R122H or N29I) in the cationic trypsinogen gene (PRSS1 gene).It has been hypothesised that one of these mutations, the R122H mutation causes pancreatitis by altering a trypsin recognition site so preventing deactivation of trypsin within the pancreas and prolonging its action, resulting in autodigestion.Families with these two mutations have been identified in many countries and there are also other rarer mutations, which have also been linked to hereditary pancreatitis.Patients with hereditary pancreatitis present in the same way as those with sporadic pancreatitis but at an earlier age.It is common for patients to remain undiagnosed for many years, particularly if they present with non-specific symptoms.Hereditary pancreatitis should always be considered in patients who present with recurrent pancreatitis with a family history of pancreatic disease.If patients with the 2 common mutations are compared, those with the R122H mutation are more likely to present at a younger age and are more likely to require surgical intervention than those with N29I.Hereditary pancreatitis carries a 40 % lifetime risk of pancreatic cancer with those patients aged between 50 to 70 being most at risk in whom screening tests may become important.
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