The observation that only a minority of heavy drinkers develop
pancreatitis has prompted an intensive search for a trigger factor/cofactor/susceptibility factor that may precipitate a clinical attack. Putative susceptibility factors examined so far include diet, smoking, amount and type of alcohol consumed, the pattern of drinking and
lipid intolerance. In addition, a range of inherited factors have been assessed including
blood group antigens,
human leukocyte antigen serotypes, alpha-1-antitrypsin phenotypes and several genotypes. The latter group comprises mutations/polymorphisms in genes related to alcohol-metabolizing
enzymes, detoxifying
enzymes, pancreatic digestive
enzymes, pancreatic
enzyme inhibitors,
cystic fibrosis and
cytokines. Disappointingly, despite this concerted research effort, no clear association has been established between the above factors and
alcoholic pancreatitis. Experimentally, the
secretagogue cholecystokinin (CCK) has been investigated as a candidate 'trigger' for
alcoholic pancreatitis. However, the clinical relevance of CCK as a trigger factor has to be questioned, as it is difficult to envisage a situation in humans where abnormally high levels of CCK would be released into the circulation to trigger
pancreatitis in alcoholics. In contrast, bacterial
endotoxemia is a candidate cofactor that does have relevance to the clinical situation. Plasma
lipopolysaccharide (LPS, an
endotoxin) levels are significantly higher in drinkers (either after chronic alcohol intake or a single binge) compared to non-drinkers. We have recently shown that alcohol-fed animals challenged with otherwise innocuous doses of LPS exhibit significant pancreatic injury. Moreover, repeated LPS exposure in alcohol-fed rats leads to progressive injury to the gland characterized by significant pancreatic
fibrosis. These studies support the concept that
endotoxin may be an important factor in the initiation and progression of
alcoholic pancreatitis. Scope remains for further studies examining
proteins related to cellular
anti-oxidant defenses, minor
cystic fibrosis (CF) mutations and trans-heterozygosity involving a combination of mutations of different genes (such as CFTR alterations combined with
SPINK1 or PRSS1 variants), as potential triggers of
alcoholic pancreatitis.