Mutation Analysis

The development of chronic pancreatitis is the end-result of a process whereby recurrent acute pancreatitis events occur because of increased susceptibility, triggering events and the development of a fibrotic and destructive response. Pancreatitis may develop as the result of both intra-acinar or intraductal events. Molecular techniques applied to groups of patients and families with a high prevalence of pancreatitis are yielding information as to mechanisms whereby gene mutations increase susceptibility in the development of acute pancreatitis events. In the pancreatic parenchymal cells an imbalance in the activation of proteases and their inhibition may be integral to the process. Small amounts of active trypsin are normally generated from its inactive precursor, most notably cationic trypsino-gen. Trypsin molecules are kept in check by protease inhibitors, such as serine protease inhibitor Kazal type 1 (ie, SPINK1; also known as pancreatic secretory trypsin inhibitor or PST1) and autolysis. However, when 10 to 20% of cationic trypsinogen (ie, protease, serine 1; PRSS1) becomes activated, the inhibitory SPINK1 mechanism becomes overwhelmed and a cascade of events can follow with the end result of pancreatitis (Whitcomb, 2002; Witt, 2003; Naruse, 2003). Some mutations in PRSS1 (eg, arginine-histidine substitution at residue 122 [R122H]) result in increased autoactivation and yield a trypsin resistant to autolysis, whereas other mutations, such as the asparagine-isoleucine substitution at residue 29 (N29I), appear to have increased autoactivation only. Mutations in SPINK1 (eg, asparagines-serine substitution at residue 34-N34S) result in loss of the SPINK1 line of defense resulting in more intracellular trypsin. it is the acinar ductal cells where expression of CFTR occurs. CFTR mutations have been classified by the CF genetic analysis into various classes based on their predicted molecular dysfunction, and there are a number of proposed mechanisms whereby pancreatitis can develop based on the fluid and electrolyte alterations in the duct with the resultant effect of acinar inflammation (Freedman et al, 2000). Disparate clinical consequences might be predicted at different gene muta tion sites but interestingly any given mutation has a spectrum of phenotypic expression. A number of mutations in the above 3 genes have been described, including over 1,000 for CFTR and around 10 so far for PRSS1 and SPINK1 (http://archive .uwcm.ac.uk/uwcm/mg/hgmd0.html). The spectrum of phenotypic expression between individuals remains unexplained but may be as a result of combinations of mutations. For instance, CF individuals homozygous for the most common CFTR mutation (deletion of the phenylalanine residue at position 508 [ie, AF508]) have evidence of pancreatitis early in life (fetal and neonatal) and generally are pancreatic insufficient. individuals that present with chronic pancreatitis rather than typical CF manifestations may be compound heterozygotes for CFTR (Cohn et al, 2002). As well, there may be synergism with non- CFTR gene modifiers. For instance, mutational analysis of patients with chronic pancreatitis has yielded individuals trans-heterozygous for a CFTR mutation and a mutation in SPINK1 (Audrezet et al, 2002; Noone et al, 2001). Thus, mutations in genes associated with pancreatic functioning can create an environment in the pancreas that modifies responses to pancreatic insults and places individuals at risk of developing pancreatitis. Then, other processes lead to the development of chronic pancreatitis and tissue destruction.

Constipation Prescription

Constipation Prescription

Did you ever think feeling angry and irritable could be a symptom of constipation? A horrible fullness and pressing sharp pains against the bladders can’t help but affect your mood. Sometimes you just want everyone to leave you alone and sleep to escape the pain. It is virtually impossible to be constipated and keep a sunny disposition. Follow the steps in this guide to alleviate constipation and lead a happier healthy life.

Get My Free Ebook


Post a comment