Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1389183 (autodigestion)
 317 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mechanism leading to exocrine pancreatic disease in children differs from those encountered in adult patients: I. In acute pancreatitis autodigestion of the gland by proteolytic enzymes may occur and two mechanisms may play a role. 1. Reflux of biliary secretions (e.g. in malformations of the duct system) facilitates activation of trypsinogen by enteropeptidase and leads to the presence of active proteolytic enzymes in the gland (exogenous activation). 2. Lysosomal enzymes may play a role in the intracellular activation of zymogens if inflammation leads to a fusion of lysosomes with zymogen granules (endogenous activation). II. In chronic relapsing and hereditary pancreatitis malformations of the pancreatico-biliary duct system must be sought because surgery may be indicated (common channel syndrome and choledochal cysts). III. Among the hereditary diseases leading to pancreatic insufficiency cystic fibrosis (CF) plays the main role. Haplotype analysis has shown that two genetically different types of CF exists (PS and PI). The pancreas shows manifest insufficiency only in the PI-types which occur in more than 70% of cases but the distribution of haplotypes is different in different ethnic groups. In spite of the recent discovery of the cystic fibrosis gene the exact mechanism leading to exocrine pancreatic dysfunction in CF is not clear, but diminished chloride and bicarbonate secretion, may be the result of a disturbance in the regulation of chloride channels, on acinar or ductular level. In the Shwachman-Diamond syndrome a very severe type of exocrine insufficiency with unknown etiology is encountered at birth.
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PMID:[Physiopathology of the exocrine pancreas in children]. 269 2

It is now generally believed that pancreatitis results from pancreatic autodigestion. An inappropriate conversion of pancreatic zymogens to active enzymes within the pancreatic parenchyma is thought to initiate the inflammatory process. A key role has been attributed to the activation of trypsinogen to trypsin, converting all proteolytic proenzymes to their active form. Several gain-of-function mutations in the cationic trypsinogen gene (PRSS1) have been identified in patients with chronic pancreatitis (CP). These mutations lead to enhanced intrapancreatic trypsinogen activation. In contrast, a variant in the anionic trypsinogen (PRSS2) gene, p.G191R, has been described that mitigates intrapancreatic trypsin activity and thereby plays a protective role. Beside trypsinogen mutations, loss-of-function variants in SPINK1, encoding a pancreatic trypsin inhibitor, are strongly associated with idiopathic CP. Approximately 15-40% of patients with so-called idiopathic CP carry p.N34S on one allele or on both alleles. Chymotrypsin C (CTRC) degrades all human trypsin isoforms with high specificity. Two CTRC alterations, p.R254W and p.K247_R254del, are significantly associated with idiopathic as well as alcohol-related CP. Functional analysis of the variants revealed impaired activity and/or reduced secretion. Thus, loss-of-function mutations in CTRC predispose to pancreatitis by diminishing its protective trypsin-degrading activity. Albeit the association between CFTR, the gene mutated in cystic fibrosis, and idiopathic CP is now well established, the pathogenic mechanisms are poorly understood. Nearly 25-30% of patients carry at least one CFTR mutation, but few patients only were compound-heterozygous. Several patients, however, are trans-heterozygous for a CFTR alteration and a PRSS1, SPINK1, or CTRC variant, respectively.
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PMID:Genetics of pancreatitis: a guide for clinicians. 2152 53