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-la, 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 ( 11 P-PGF2a) were performed. Analysis looked at both acute (n= 19) and chronic pancreatitis (n= 19), employing age and sex matched controls. The L TE4 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 ANOV A p= 0.024 and direct comparison of patients with mild disease and their matched controls; p= 0.0 11. The llP-PGFza study conversely showed no difference in AP but significantly higher levels in CP in comparison to their matched controls; p= 0.00 I, Mann Whitney U test. Based on a previous pilot study in CP and a difference in variance of L TE4 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 2EI (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. 11 P-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. List of Tables and Illustrations Abbreviations used in the text Acknowledgements Authors Declaration CHAPTER I: INTRODUCTION CONTENTS Page No