2 research outputs found
GENETIC AND MOLECULAR FACTORS IN THE AETIO-PATHOGENESIS OF PANCREATITIS IN HUMANS
Both acute (AP) and chronic (CP) pancreatitis are complex diseases, with a number of
aetiologies and complex pathogeneses. A number of contributing factors are assessed here.
Genetic studies were performed looking at a high activity polymorphism of the alcohol
metabolising enzyme cytochrome P450 2E l. Assessing a role in alcohol abuse and end
organ disease; alcohol abusers (n= 239) and controls (n= 208) were studied. A significantly
lower number of alcohol consumers (2.1 %) had the polymorphism than controls (5.8%);
p= 0.049, Fisher's exact test. Any association with end organ disease could not be further
elucidated due to the rarity of the polymorphism in this population. In another genetic
study, looking at a polymorphism in interleukin-1a, no associations were found with CP; of
note no associations were found with genotypes implicated in AP.
A double-blind, placebo controlled crossover trial of a leukotriene receptor antagonist in
chronic pancreatitis revealed no benefit.
Studies of production of arachidonic acid metabolites leukotriene E4 (LTE4), prostaglandin
E2 (PGE2) and (a known marker of mast cell activation) prostaglandin D2 (11β-PGF2a)
were performed. Analysis looked at both acute (n= 19) and chronic pancreatitis (n= 19),
employing age and sex matched controls. The LTE4 studies did not reveal any significant
difference in levels. PGE2 levels were not different between CP patients and controls while
they were significantly higher in AP than controls; p= 0.006, independent samples t-test.
The variation appeared most marked for mild disease; one way ANOVA p= 0.024 and
direct comparison of patients with mild disease and their matched controls; p= 0.011. The
11β-PGF2a study conversely showed no difference in AP but significantly higher levels in
CP in comparison to their matched controls; p= 0.001, Mann Whitney U test.
Based on a previous pilot study in CP and a difference in variance of LTE4 in AP in the
above study, a genetic study of the known functional polymorphism in the gene of
leukotriene C4 synthase (the first dedicated enzyme in the formation of the cysteinyl
leukotrienes) was performed. Controls totalled 108 subjects; AP 238 (mild= 169 patients;
severe= 69) and CP 57 subjects; no difference in the genotype or allele frequencies were
found.
In summary: A possible role for a functional polymorphism in cytochrome P450 2E1 (not
previously examined in patient groups) in protection against alcoholism has been
identified. Perhaps analogous to the protection associated with high activity forms of
alcohol dehydrogenase and low activity forms of aldehyde dehydrogenase.
PGE2 is elevated in acute pancreatitis in humans consistent with the majority of the data in
animals. Again consistent with the bulk of animal data this appears to be most marked in
mild disease, possibly indicating a protective, and therefore potentially therapeutic, role.
11β-PGF2a, a metabolite of PGD2 and marker of mast cell activation, is elevated in chronic
but not acute pancreatitis. This implicates mast cells in chronic pancreatitis and would be
consistent with their known role in fibrosis and tissue remodelling and suggests a possible
therapeutic target