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Query: UMLS:C0149521 (chronic pancreatitis)
 7,199 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hereditary, chronic pancreatitis is an autosomal dominant genetic disorder, frequently associated with two point mutations in the cationic trypsinogen gene. The mutations result in characteristic changes in the amino-acid sequence of trypsinogen: an arginine residue at position 117 is changed to histidine (Arg117-->His) or an asparagine residue at position 21 is replaced by isoleucine (Asn21-->Ile). Current opinion on the pathogenesis of hereditary pancreatitis suggests that the mutations lead to increased trypsin activity in the pancreatic tissue as a result of enhanced autoactivation of trypsinogen or decreased autocatalytic degradation (autolysis) of trypsin. To investigate the relationship between the altered properties of mutant trypsinogens and the pathomechanism of pancreatitis, wild-type and two mutant forms of recombinant human cationic trypsinogen were produced and autoactivation of trypsinogens and autolysis of trypsins were studied. The results indicate that trypsin stabilization (i.e. decreased autolysis) caused by the Arg117-->His mutation may contribute to the development of pancreatitis, however, the Asn21-->Ile mutation has no such effect. In contrast, enhanced autoactivation of mutant trypsinogens may contribute to the pathogenesis of both forms of hereditary pancreatitis. This notion is strongly supported by the clear correlation between the autoactivation rates of mutant trypsinogens and the severity of clinical symptoms.
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PMID:[Significance of trypsinogen gene mutations in the etiology of hereditary pancreatitis]. 1132 17

Chronic pancreatitis (CP) is a continuing or relapsing inflammatory disease of the pancreas. Several studies have demonstrated that mutations in the cationic trypsinogen (PRSS1) gene and the cystic fibrosis transmembrane conductance regulator (CFTR) gene are causative of the pathogenesis in a subset of hereditary and/or idiopathic CP cases. Recently, the N34S alteration of the pancreatic secretory trypsin inhibitor (PSTI) gene has been suggested to be closely associated with the pathogenesis of hereditary and/or idiopathic CP. Herein we analyzed genetic alterations of the PSTI gene in 32 unrelated Japanese CP patients who developed juvenile-onset CP or had a family history of CP; 5 patients were found to harbor alterations in this gene. In 3 of these 5 patients, heterozygous N34S alterations were found; this frequency is significantly lower than that in Caucasian patients reported previously. Moreover, a novel homozygous G-to-A transition in the promoter region of PSTI at 215bp upstream from the translation initiation site (-215G>A) was observed in 2 patients. We further surveyed the -215G>A alteration in 117 normal individuals; none of these individuals harbored this alteration. Our results suggested that the -215G>A alteration, as well as the N34S alteration, is a predisposing factor for CP.
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PMID:Analysis of the human pancreatic secretory trypsin inhibitor (PSTI) gene mutations in Japanese patients with chronic pancreatitis. 1135 22

For decades there has been slow progress in understanding pancreatic diseases, particularly acute and chronic pancreatitis. As a result, there were no significant advances in the management of these patients. Treatment was mostly directed towards symptomatic relief and management of complications. A simple clinical observation that multiple members of a large family are affected by acute and chronic pancreatitis, some at very young age and in the absence of any alcohol use, led physician-scientists of the Midwest Multicenter Pancreatic Study Group (investigators from the University of Cincinnati, University of Kentucky, and University of Pittsburgh) to investigate the genetic basis of hereditary pancreatitis. Using information from the human genome project, the hereditary pancreatitis gene was identified as the cationic trypsinogen gene (protease serine 1, PRSS1). This discovery has led to the identification of a number of other genes and their products playing role in the pathogenesis of acute and chronic pancreatitis. In the emerging picture of pathogenesis of acute and chronic pancreatitis, trypsin appears to play a central role. This newly acquired knowledge is setting the stage for new preventive and management strategies for hereditary and sporadic acute and chronic pancreatitis.
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PMID:Lessons from hereditary pancreatitis. 1147 Dec 4

Summary. The understanding of the pathogenesis of chronic pancreatitis is limited. Several theories (i. e. obstruction hypothesis) were suggested in the past but could not be confirmed by experimental data. As a formal description of the course of the disease, the necrosis-fibrosis concept seems to be very attractive. According to this theory, there is no significant difference in the pathogenesis of acute and chronic pancreatitis. A major step was the identification of mutations of the cationic trypsinogen, the secretory trypsin inhibitor (SPINK 1) and the cystic-fibrosis protein (CFTR) in some patients. Investigation of these mutations may significantly contribute to a better understanding of the pathogenesis of chronic pancreatitis.
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PMID:[Pathogenetic concepts of chronic pancreatitis]. 1175 98

Hereditary pancreatitis is due to heterozygosity for gain-of-function mutations in the cationic trypsinogen gene which result in increased levels of active trypsin within pancreatic acinar cells and autodigestion of the pancreas. The number of disease-causing defects is generally considered to be low. To gain further insight into the molecular basis of this disorder, DNA sequence analysis of all five exons was performed in 109 unrelated patients with idiopathic chronic pancreatitis in order to determine the variability of the underlying mutations. Two German females and one German male were carriers of the most common N29I and R122H mutations (trypsinogen numbering system). In a Turkish proband, an arginine (CGT) to cysteine (TGT) substitution at amino acid position 116 was identified. Family screening demonstrated that the patient had inherited the mutation from his asymptomatic father and that he had transmitted it to both of his children, his daughter being symptomatic since the age of 3 years. In addition, a German male was found to be a heterozygote for a D100H (GAC-->CAC) amino acid replacement. Our data provide evidence for genetic heterogeneity of hereditary pancreatitis. The growing number of cationic trypsinogen mutations is expected to change current mutation screening practices for this disease.
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PMID:R116C mutation of cationic trypsinogen in a Turkish family with recurrent pancreatitis illustrates genetic microheterogeneity of hereditary pancreatitis. 1184 79

We report a 25-year-old male with hemosuccus pancreaticus associated with hereditary pancreatitis. He was originally diagnosed as having familial chronic pancreatitis at the age of 12, because his brother was also diagnosed as having pancreatitis. No history of pancreatitis was found in their parents. The patient was admitted because of a growing pancreatic pseudocyst. While he had undergone conservative treatment for the pseudocyst, computed tomography incidentally revealed a pancreatic pseudoaneurysm. Endoscopic examination revealed spontaneous bleeding from the major papilla. Interventional embolization was successfully performed. An R122H mutation in the cationic trypsinogen gene was identified in this patient, his brother, and his mother, indicating that they have hereditary pancreatitis. To our knowledge, this is the first report of hemosuccus pancreaticus associated with hereditary pancreatitis. Mutational screening is useful for the diagnosis of hereditary pancreatitis, especially in patients whose diagnosis is inconclusive based on the traditional clinical criteria.
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PMID:A case of hemosuccus pancreaticus associated with hereditary pancreatitis. 1187 52

In the last 5 years, mutations in three genes, the cystic fibrosis transmembrane conductance regulator (CFTR) gene, the cationic trypsinogen (PRSS1) gene, and the pancreatic secretory trypsin inhibitor (PSTI) gene, have been found to be associated with chronic pancreatitis (CP). In this study, using established mutation screening methods, we systematically analysed the entire coding sequences and all exon/intron junctions of the three genes in 39 patients with idiopathic CP (ICP), with a view to evaluating the relative contribution of each gene to the aetiology of the disease. Our results demonstrate that, firstly, 'gain-of-function' mutations in the PRSS1 gene may occasionally be found in an obvious ICP subject. Secondly, presumably 'loss-of-function' mutations in the PSTI gene appear to be frequent, with a detection rate of at least 10% in ICP and, finally, abnormal CFTR alleles are common: at least 20% of patients carried one of the most common CFTR mutations, and about 10% of patients were compound heterozygotes, having at least one 'mild' allele. Thus, in total, about 30% of ICP patients carried at least one abnormal allele in one of the three genes, and this is the most conservative estimate. Moreover, a trans-heterozygous state with sequence variations in the PSTI/CFTR genes was found in three patients. However, an association between the 5T allele in intron 8 of the CFTR gene and ICP remains unproven.
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PMID:Determination of the relative contribution of three genes-the cystic fibrosis transmembrane conductance regulator gene, the cationic trypsinogen gene, and the pancreatic secretory trypsin inhibitor gene-to the etiology of idiopathic chronic pancreatitis. 1263 55

Progress in understanding pancreatic diseases has been limited by a number of factors. Primary problems include the absence of good animal models, and difficulty in understanding the origin of pancreatic disease since the disease is usually manifest by the progressive destruction of the gland itself. Beginning in 1995, our laboratory, with the support of the Midwest Multicenter Pancreatic Study Group, began investigating the genetic basis of hereditary pancreatitis. Utilization of information becoming available through the human genome project allowed us to map and identify the hereditary pancreatitis gene as cationic trypsinogen (PRSS1). Molecular modeling, and subsequent experimental evidence, has solved key elements of the mysteries surrounding the origin of acute pancreatitis and the progression of acute pancreatitis to chronic pancreatitis. The availability of new genetic information and genomic tools should produce a revolution in our understanding of pancreatic diseases.
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PMID:Hereditary pancreatitis: a model for understanding the genetic basis of acute and chronic pancreatitis. 1212 Feb 37

We present a case of 2 brothers with idiopathic chronic pancreatitis associated with pancreatic duct stones which could be successfully disintegrated by extracorporeal shock wave lithotripsy (ESWL). An obvious etiology for the pancreatolithiasis, like alcohol or biliary disease, was lacking and point mutations of the cationic trypsinogen gene exons 2 and 3 were not detected in the long arm of the 7th chromosome. However, a hereditary etiology could not be precluded since pancreatolithiasis occurred in the siblings. There has been no recurrence of pancreatic stones during 42 months of follow-up periods, for both. ESWL, the least invasive therapy, appeared applicable and effective for pancreatolithiasis in the present cases.
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PMID:Successful extracorporeal shock wave lithotripsy for sibling pancreatic duct stones. 1212 Feb 71

Mutations in the cationic trypsinogen, cystic fibrosis transmembrane conductance regulator (CFTR) and pancreatic secretory trypsinogen inhibitor (PSTI) genes have recently been associated with chronic pancreatitis. This paper investigates the frequency of CFTR and PSTI gene mutation in patients with idiopathic and alcoholic chronic pancreatitis, the clinical course of patients with these two kinds of disease, and examines the clinical differences between carriers and noncarriers of mutation. In idiopathic pancreatitis a significant increase was found in mutation frequency both in the CFTR gene (13%) and N34S mutation in the PSTI gene (3.9%), as well as an increase in familial disposition to pancreatic disorders. In alcohol-induced pancreatitis an increase in calcification, exocrine insufficiency, and diabetes mellitus was observed. In conclusions, mutations in the genes investigated are involved in causing idiopathic pancreatitis. Such mutations have no connection either with the age at onset or the clinical course of the disease.
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PMID:Germline mutations in CFTR and PSTI genes in chronic pancreatitis patients. 1245 72


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