Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0149521 (chronic pancreatitis)
 7,199 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Classic cystic fibrosis (CF) is caused by two loss-of-function mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, whereas patients with nonclassic CF have at least one copy of a mutant gene that retains partial function of the CFTR protein. In addition, there are several other phenotypes associated with CFTR gene mutations, such as idiopathic chronic pancreatitis. In CFTR-associated disorders and in nonclassic CF, often only one CFTR mutation or no CFTR mutations can be detected. In this study, we screened 23 patients with CFTR-associated disorders for CFTR mutations by complete gene testing and quantitative transcript analysis. Mutations were found in 10 patients. In cells from respiratory epithelium, we detected aberrant splicing of CFTR mRNA in all investigated individuals. We observed a highly significant association between the presence of coding single-nucleotide polymorphisms (coding SNPs, or cSNPs) and increased skipping of exon 9 and 12. This association was found both in patients and in normal individuals carrying the same cSNPs. The cSNPs c.1540A>G, c.2694T>G, and c.4521G>A may have affected pre-mRNA splicing by changing regulatory sequence motifs of exonic splice enhancers, leading to lower amounts of normal transcripts. The analysis of CFTR exons indicated that less frequent and weak exonic splicing enhancer (ESE) motifs make exon 12 vulnerable to skipping. The number of splice variants in individuals with cSNPs was similar to previously reported values for the T5 allele, suggesting that cSNPs may enhance susceptibility to CFTR related diseases. In addition, cSNPs may be responsible for variation in the phenotypic expression of CFTR mutations. Quantitative approaches rather than conventional genomic analysis are required to interpret the role of cSNPs.
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PMID:The role of common single-nucleotide polymorphisms on exon 9 and exon 12 skipping in nonmutated CFTR alleles. 1524 93

Pancreatic inflammation appears to increase the risk of pancreatic cancer. This observation is striking in the hereditary pancreatitis kindreds but also occurs in alcoholic, idiopathic, and tropical chronic pancreatitis and cystic fibrosis. However, the mutations associated with hereditary pancreatitis or cystic fibrosis are not found in sporadic pancreatic adenocarcinomas, suggesting that the effects are indirect by causing recurrent pancreatitis and chronic inflammation. The process of mutation accumulation and clonal expansion that is required for development of invasive pancreatic adenocarcinoma must therefore be accelerated in chronic pancreatitis to account for the high incidence of pancreatic cancer in these patients.
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PMID:Inflammation and Cancer V. Chronic pancreatitis and pancreatic cancer. 1524 66

The pathogenesis of idiopathic chronic pancreatitis remains poorly understood despite the high expectations for ascribing the pancreatic damage in affected patients to genetic defects. Mutations in the cationic trypsinogen gene, pancreatic secretory trypsin inhibitor, and the cystic fibrosis conductance regulator gene do not account for the chronic pancreatitis noted in most patients with idiopathic chronic pancreatitis. Small duct chronic pancreatitis can be best diagnosed with a hormone stimulation test. Endoscopic ultrasonography can detect abnormalities in both the parenchyma and ducts of the pancreas. The true value of endoscopic ultrasonography in diagnosing small duct chronic pancreatitis remains to be fully defined and is under active investigation. It is not clear whether endoscopic ultrasonography is more sensitive for early structural changes in patients with small duct disease or is over diagnosing chronic pancreatitis. Pancreatic enzyme supplementation with non-enteric formulation along with acid suppression (H2 blockers or proton pump inhibitors) is an effective therapy for pain in patients with small duct chronic pancreatitis. The role of endoscopic ultrasonography-guided celiac plexus block should be limited to treating those patients with chronic pancreatitis whose pain has not responded to other modalities. Total pancreatectomy followed by autologous islet cell autotransplantation appears to be potential therapeutic approach but for now should be considered experimental.
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PMID:Chronic pancreatitis: controversies in etiology, diagnosis and treatment. 1550 8

The purpose of this manuscript is to provide an overview of the normal development of the pancreas as well as pancreatic pathology in children. Diagnostic imaging plays a major role in the evaluation of the pancreas in infants and children. Familiarity with the range of normal appearance and the diseases that commonly affect this gland is important for the accurate and timely diagnosis of pancreatic disorders in the pediatric population. Normal embryology is discussed, as are the most common congenital anomalies that occur as a result of aberrant development during embryology. These include pancreas divisum, annular pancreas, agenesis of the dorsal pancreatic anlagen and ectopic pancreatic tissue. Syndromes that can manifest pancreatic pathology include: Beckwith Wiedemann syndrome, von Hippel-Lindau disease and autosomal dominant polycystic kidney disease. Children and adults with cystic fibrosis and Shwachman-Diamond syndrome frequently present with pancreatic insufficiency. Trauma is the most common cause of pancreatitis in children. In younger children, unexplained pancreatic injury must always alert the radiologist to potential child abuse. Pancreatic pseudocysts are a complication of trauma, but can also be seen in the setting of acute or chronic pancreatitis from other causes. Primary pancreatic neoplasms are rare in children and are divided into exocrine tumors such as pancreatoblastoma and adenocarcinoma and into endocrine or islet cell tumors. Islet cell tumors are classified as functioning (insulinoma, gastrinoma, VIPoma and glucagonoma) and nonfunctioning tumors. Solid-cystic papillary tumor is probably the most common pancreatic tumor in Asian children. Although quite rare, secondary tumors of the pancreas can be associated with certain primary malignancies.
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PMID:Disorders of the pediatric pancreas: imaging features. 1553 62

The classical feature of hereditary pancreatitis (HP) is characterized by recurrent episodes of acute pancreatitis or a priori chronic pancreatitis in several members of one family. In 1996, the identification of the first HP-associated mutation in the cationic trypsinogen gene provided a breakthrough in our understanding of the pathogenesis of chronic pancreatitis. In the following years, several different mutations in the same gene have been found in a large number of investigated families. Most intriguing, HP patients have a more than 50-fold increased risk of pancreatic ductal cancer in comparison with expected pancreatic cancers in the general population. Variants of the major intrapancreatic trypsin antagonist SPINK1 have implications for more common forms of chronic pancreatitis. Research has focussed on the SPINK1-N34S-mutation, which is closely associated with tropical, alcoholic, or "idiopathic" chronic pancreatitis. Chronic pancreatitis represents a variable part of the cystic fibrosis syndrome, which is caused by mutations in the gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR). Several groups have reported an increased prevalence of CFTR mutations in patients with chronic pancreatitis of different etiology. In this review, we summarize interesting clinical and biochemical features of genetic variants in these genes which are associated with chronic pancreatitis.
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PMID:Genetic aspects of chronic pancreatitis. 1556 96

Idiopathic chronic pancreatitis (ICP) is the leading cause of chronic pancreatitis in children and nonalcoholic adults. The risk of developing ICP is increased in individuals who have mutations of the cystic fibrosis gene (CFTR) and of a trypsin inhibitor gene (PSTI). In studies from the United States and France, the risk of ICP is increased about 40-fold by having two abnormal copies of the CFTR gene, about 14-fold by having the N34S PSTI mutation, and about 500-fold by having both. When ICP patients have two abnormal copies of the CFTR gene, there is also evidence of reduced residual CFTR protein function in extrapancreatic tissues based on clinical findings and nasal ion transport responses. Thus, pancreatitis risk is highest in individuals who have abnormalities in both the pancreatic ducts (CFTR) and acini (PSTI). These findings indicate that PSTI is a modifier gene for CFTR-related ICP and have implications for the diagnosis and pathogenesis of pancreatitis.
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PMID:Reduced CFTR function and the pathobiology of idiopathic pancreatitis. 1575 63

It has been more than 15 years since the epidemiological studies revealed the interrelation between chronic pancreatitis (CP) and pancreatic cancer (PC). For the specified period of time pancreatology has advanced considerably. The genetic nature of mucoviscidosis and hereditary pancreatitis was revealed, and similar studies were carried out with respect to pancreatic cancer as well. As a result, several genetic processes were revealed, some of them promoting the development of a chronic inflammatory process in the pancreas, and others--malignant changes. It was established later that in some cases pancreatic cancer can have a precisely inherited nature being associated with other hereditary syndromes, yet the frequency of this form of pancreatic cancer does not exceed 3%, while some forms of chronic pancreatitis (hereditary and tropical) increase the risk of development of pancreatic cancer in 53-100 times.
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PMID:[Epidemiological and molecular-genetic aspects of the association between chronic pancreatitis and pancreatic cancer]. 1593 49

Chronic pancreatitis: Only recently mutations in several genes were found in patients with chronic pancreatitis. In those with a familial chronic pancreatitis mutations of the cationic trypsinogen were identified and the variants N29I and R122H lead to an autosomal dominant disease. In this group of patients the mutation N34S of the trypsin inhibitor SPINK1 was detected. In so-called idiopathic pancreatitis both variants of the SPINK1 and of the CFTR (cystic fibrosis transmembrane conductance regular) were identified. Alterations in both genes were also found in patients with alcoholic chronic pancreatitis. The strongest risk factor for chronic pancreatitis were trypsinogen mutations N29I and R122H mutations. However, both SPINK1 and CFTR increased the risk for chronic pancreatitis to a higher level than alcohol consumption. A genetic investigation should be performed in familial disease and younger age, but also in patients without family history and higher age a mutation could be found. Pancreas cancer: In 10% of the patients with pancreas cancer other members of the family were affected from the disease. Some of them belong to well characterized familial syndroms like HNPCC or Peutz-Jeghers-syndrom. In a minority of the others a genetic factor may be found, too. In sporadic disease the development of the tumor is characterized by continued acquirement of genetic alterations described by the PanIN model (pancreatic intraepithelial neoplesia). This means that the evolution of the neoplasia progresses from normal tissue via epithelial hyperplasy (PanIN 1A), papillary hyperplasy without (PanIN 1B) and with dysplasy (PanIN 2) and carcinoma in situ (PanIN 3) to invasive pancreas cancer. The progression is associated with genetic alterations of the cells (mutations of ki-ras, p16, p53 etc.). This results in deterioration of control of the cell cycle and the apoptosis and explains the malignancy of the disease. These findings may be used in the future to develop newer therapeutic principles in order to improve the dismal prognosis of this disease.
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PMID:[Chronic pancreatitis--pancreas cancer: influence of genetic factors]. 1595 15

Cystic fibrosis (CF) is a recessive disease caused by mutations of the CF transmembrane conductance regulator (CFTR) gene. The risk of idiopathic chronic pancreatitis (ICP) is increased in individuals who have CFTR genotypes containing a CF-causing mutation plus a second pathogenic allele. It is unknown whether the risk of ICP is increased in CF carriers who have one CF-causing mutation plus one normal allele. In this study, 52 sporadic cases of ICP were ascertained through the European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer. Individuals with pathogenic cationic trypsinogen mutations were excluded. DNA was comprehensively tested for CFTR mutations using a robotically enhanced, multiplexed, and highly redundant form of single-strand conformation polymorphism (SSCP) analysis followed by DNA sequencing. Fifteen subjects had a total of 18 pathogenic CFTR alleles. Eight subjects had common CF-causing mutations. This group included seven CF carriers in whom the second CFTR allele was normal (4.3 times the expected frequency, P=0.0002). Three subjects had compound heterozygotes genotypes containing two pathogenic alleles (31 times the expected frequency, P<0.0001). A variant allele of uncertain significance (p.R75Q) was detected in eight of the 52 ICP subjects and at a similar frequency (13/96) in random donors. ICP differs from other established CFTR-related conditions in that ICP risk is increased in CF carriers who have one documented normal CFTR allele. Having two CFTR mutations imparts a higher relative risk, while having only one mutation imparts a higher attributable risk.
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PMID:Increased risk of idiopathic chronic pancreatitis in cystic fibrosis carriers. 1613 71

Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations are associated with cystic fibrosis (CF)-related monosymptomatic conditions, including idiopathic pancreatitis. We evaluated prospectively enrolled patients who had idiopathic recurrent acute pancreatitis or idiopathic chronic pancreatitis, healthy controls, CF heterozygotes, and CF patients (pancreatic insufficient or sufficient) for evidence of CFTR gene mutations and abnormalities of ion transport by sweat chloride and nasal potential difference testing. DNA samples from anonymous blood donors were controls for genotyping. At least one CFTR mutation or variant was carried in 18 of 40 patients (45%) with idiopathic chronic pancreatitis and in 6 of 16 patients (38%) with idiopathic recurrent acute pancreatitis but in only 11 of the 50 controls (22%, P=0.005). Most identified mutations were rare and would not be identified in routine genetic screening. CFTR mutations were identified on both alleles in six patient (11%). Ion transport measurements in patients with pancreatitis showed a wide range of results, from the values in patients with classically diagnosed CF to those in the obligate heterozygotes and healthy controls. In general, ion channel measurements correlated with the number and severity of CFTR mutations. Twelve of 56 patients with pancreatitis (21%) fulfilled current clinical criteria for the diagnosis of CF, but CFTR genotyping alone confirmed the diagnosis in only two of these patients. We concluded that extensive genotyping and ion channel testing are useful to confirm or exclude the diagnosis of CF in the majority of patients with idiopathic pancreatitis.
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PMID:The cystic fibrosis transmembrane conductance regulator gene and ion channel function in patients with idiopathic pancreatitis. 1619 25


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