Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030305 (pancreatitis)
 16,014 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The discovery of PRSS1 mutations in hereditary pancreatitis and analysis of how the genotype affects the presentation and progression of hereditary pancreatitis has led to a better understanding of the pathophysiology of the disease. Patients with hereditary pancreatitis present with symptoms at an early age and have a significant lifetime risk for the development of endocrine and exocrine insufficiency, albeit at a later stage than patients with either idiopathic or alcoholic chronic pancreatitis. There are distinct phenotypic differences between hereditary pancreatitis and with other types of pancreatitis. As many as 80% of patients with symptomatic hereditary pancreatitis have an underlying causative PRSS1 mutation; there are, however, few significant phenotypic differences between these PRSS1 mutations. The R122H mutation is the most common PRSS1 mutation observed, and patients with the R122H mutation present earlier. This, however, does not necessarily translate into a more aggressive disease with respect to complications of chronic pancreatitis. Indeed, the age of presentation of symptoms may be a poor surrogate for predicting outcome, as inherited disorders of trypsinogen may cause subclinical attacks of pancreatitis, which ultimately lead to pancreatic destruction and dysfunction. All patients, irrespective of whether they carry a PRSS1 mutation, are at significant risk of developing pancreatic ductal adenocarcinoma. The risk appears to be insignificant below the age of 40 years, but it increases incrementally thereafter. Significantly, the risk of pancreatic cancer is not related to PRSS1 mutation type and does not appear to be related to the mode of inheritance. The role of SPINK1 mutations in modifying the expression of PRSS1 mutations is unclear but appears to be of clinical importance. It is unlikely that they act as causative mutations per se, at least in the Western form of the disease. Additionally, they do not appear to have an impact on the penetrance of PRSS1 gene mutations in hereditary pancreatitis.
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PMID:Cationic trypsinogen mutations and pancreatitis. 1552 17

In summary, SPINK1 is thought to play an important role in protecting the pancreas against excessive trypsinogen activation. SPINK1 mutations are associated with the development of acute and chronic pancreatitis and have been detected in all forms of chronic pancreatitis. The strong association of mutations in the PRSS1 gene and in the SPINK1 gene with chronic pancreatitis supports the concept of intracellular trypsin activation as an initiating and extremely important step in the development of pancreatitis. The N34S mutation represents the most frequently observed pancreatitis-associated SPINK1 variant. Because the SPINK1 N34S mutation is very common in the general population, it is unlikely that this mutation alone can initiate the development of chronic pancreatitis. Thus, it rather appears that in most patients with SPINK1-associated chronic pancreatitis, this genetic variant acts as disease modifier or within a polygenic model with other yet unidentified genes or environmental cofactors. The possible interaction of mutations in the SPINK1 gene with other pancreatitis-associated susceptibility genes has to be investigated in future research efforts. The most promising candidate gene for such an interaction is the CFTR gene, because genetic alterations within the CFTR gene are also common in the general population and already have been associated with chronic pancreatitis.
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PMID:Serine protease inhibitor Kazal type 1 mutations and pancreatitis. 1552 18

This article summarized several observations on the role of pancreatic secretory trypsin inhibitor in the pancreas. Although it long has been suspected that endogenous pancreatic trypsin inhibitors protect against inadvertent activation of trypsinogen, this hypothesis has gained strength from recent biochemical investigations and genetic studies of populations suffering from chronic pancreatitis. There is now considerable evidence from clinical disease associations and burgeoning experimental models that some forms of pancreatitis may be the result of an imbalance between active pancreatic proteases and their inhibitors within the pancreas. Future studies should clarify the precise molecular interactions between enzymes and inhibitors and how these may be manipulated to prevent or treat pancreatitis.
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PMID:Susceptibility to pancreatitis related to PSTI/SPINK1 expression. 1552 19

The importance of pretest information, using an accredited DNA laboratory and interpreting the genotype on behalf of the patient and their physicians is emphasized. Care with predictive testing and the strong encouragement to involve a specialist genetic counseling service is made. A similar approach to genetic testing should be used when children are involved. Because of the incomplete pickup of PRSS1 mutations, particularly of a limited mutation panel of R122H and N291 (perhaps with A16V), a diagnosis of HP cannot be ruled out by molecular genetic testing alone. The A16V mutation has a reduced penetrance, and its contribution to pancreatitis remains unclear. The advice to patients with genetic forms of pancreatitis is a strong encouragement to avoid smoking, to avoid alcohol, and to remain in contact with clinical and research groups for their follow-up and screening trials for early pancreatic cancer. The remaining issues are of how wide to cast the net of investigation in patients with unexplained pancreatitis, particularly looking for mutations in the CFTR and lower penetrance genes such as PSTI/SPINK1.
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PMID:Genetic counseling for hereditary pancreatitis--the role of molecular genetics testing for the cationic trypsinogen gene, cystic fibrosis and serine protease inhibitor Kazal type 1. 1552 21

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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PMID:[Pancreatitis-associated gene mutations]. 1555 98

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

The identification of a specific mutation in the human cationic trypsinogen gene in large kindreds with hereditary pancreatitis was the key to understand the genetic background of chronic pancreatitis. Rapidly, other variants within the same gene were identified-even in small families with a minority of patients. Later, mutations of the most important intrapancreatic trypsin inhibitor SPINK1 were found with high prevalence in patients with idiopathic, tropical and alcoholic chronic pancreatitis. We summarize interesting genetic and biochemical findings, point to clinical features and review recommendations for genetic analysis, follow-up and cancer prevention.
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PMID:[Clinical implications of genetic risk factors of chronic pancreatitis]. 1565 84

Considerable progress in the understanding of the pathogenesis of acute pancreatitis is based on the conclusive finding that the initiation of the disease occurs within the acinar cell. Two lines of evidence have contributed to the progress in understanding the disease process: (1) the identification of patients with a hereditary form of pancreatitis as carriers of germline-mutations in the genes for cationic trypsinogen and the pancreatic secretory trypsin inhibitor and (2) the use of various transgenic and knock-out mouse strains in experimental models of acute pancreatitis. On the other hand, these studies have delivered several unexpected results that appear to be incompatible with long-standing dogmas and paradigms of pancreatic research. Further progress in knowledge will result if the well-characterized enzymatic properties of human enzymes that are involved in the initial activation cascade can be investigated under in vivo conditions in transgenic animals or in permanent acinar cell lines. Such studies will permit the development of effective strategies for the prevention and treatment of this disease.
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PMID:Early events in acute pancreatitis. 1574 29

The discovery of PRSS 1 mutations in hereditary pancreatitis and analysis of how the genotype affects the presentation and progression of hereditary pancreatitis has led to a better understanding of the pathophysiology of the disease. Patients with hereditary pancreatitis present with symptoms at an early age and have a significant lifetime risk for the development of endocrine and exocrine insufficiency, albeit at a later stage than patients with either idiopathic or alcoholic chronic pancreatitis. There are distinct phenotypic differences between hereditary pancreatitis and with other types of pancreatitis. As many as 80% of patients with symptomatic hereditary pancreatitis have an underlying causative PRSS1 mutation; there are, however, few significant phenotypic differences between these PRSS1 mutations. TheR122H mutation is the most common PRSS1 mutation observed, and patients with the R122H mutation present earlier. This, however, does not necessarily translate into a more aggressive disease with respect to complications of chronic pancreatitis. Indeed, the age of presentation of symptoms may be a poor surrogate for predicting outcome, as inherited disorders of trypsinogen may cause subclinical attacks of pancreatitis, which ultimately lead to pancreatic destruction and dysfunction. All patients, irrespective of whether they carry a PRSS1 mutation, are at significant risk of developing pancreatic ductal adenocarcinoma. The risk appears to be insignificant below the age of 40 years, but it increases incrementally thereafter. Significantly, the risk of pancreatic cancer is not related to PRSS1 mutation type and does not appear to be related to the mode of inheritance. The role of SPINK1 mutations in modifying the expression of PRSS1mutations is unclear but appears to be of clinical importance. It is unlikely that they act as causative mutations per se, at least in the Western form of the disease. Additionally, they do not appear to have an impact on the penetrance of PRSS1 gene mutations in hereditary pancreatitis.
 ...
PMID:Cationic trypsinogen mutations and pancreatitis. 1574 31

SPINKI is thought to play an important role in protecting the pancreas against excessive trypsinogen activation. SPINK1 mutations are associated with the development of acute and chronic pancreatitis and have been detected in all forms of chronic pancreatitis. The strong association of mutations in the PRSS1 gene and in the SPINKI gene with chronic pancreatitis supports the concept of intracellular trypsin activation as an initiating and extremely important step in the development of pancreatitis. The N34S mutation represents the most frequently observed pancreatitis-associated SPINKI variant. Because the SPINKI N34Smutation is very common in the general population, it is unlikely that this mutation alone can initiate the development of chronic pancreatitis. Thus, it rather appears that in most patients with SPINKI-associated chronic pancreatitis, this genetic variant acts as disease modifier or within a polygenic model with other yet unidentified genes or environmental co-factors. The possible interaction of mutations in the SPINK1 gene with other pancreatitis-associated susceptibility genes has to be investigated in future research efforts. The most promising candidate gene for such an interaction is the CFTR gene, because genetic alterations within the CFTRgene are also common in the general population and already have been associated with chronic pancreatitis.
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PMID:Serine protease inhibitor kazal type 1 mutations and pancreatitis. 1574 32


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