Over the last decades there have been numerous efforts to elucidate the mechanisms by which alcohol damages the pancreas.
The injurious effects of ethanol on the pancreas are mediated through different mechanisms[71
] as (1) sensitization of acinar cells to cholecystokinin (CCK) inducing premature activation of zymogens[72
]; (2) potentiation of the effect of CCK on the activation of transcription factors, nuclear factor-ĸB and activating protein-1[73,74
]; (3) generation of toxic metabolites such as acetaldehyde and fatty acid ethyl esters; (4) sensitization of the pancreas to the toxic effects of coxsackievirus B3[75
]; and (5) activation of pancreatic stellate cells by acetaldehyde and oxidative stress and subsequent increased production of collagen and other matrix proteins[76
Chronic alcohol exposure leads to impaired exocytosis mediated by acetaldehyde-induced microtubular dysfunction and apical cytoskeleton reorganization in acinar cells, with a subsequent accumulation of intracellular enzymes[77
]. In addition, alcohol decreases the stability of zymogen and lysosomal membranes and enhancers acinar cell sensibility to CCK further increasing susceptibility to pathological enzyme activation[78,79
]. Some theories also show that physiologically ethanol leads to the formation of protein secretory plugs that obstruct pancreatic ducts, spam of the sphincter of Oddi or decreased tone of the sphincter causing reflux[80-82
Ethanol and its major metabolite, acetaldehyde, are classified by the International Agency for Research on Cancer as group 1 carcinogens[83
Alcohol metabolism depends on enzymes that transform ethanol. Genes for these modifying enzymes have specific polymorphisms that differ between subjects and races leading to differences in susceptibility to alcohol effects and alcohol dependence[47
Although the liver is the major ethanol-metabolizing organ in the body, the pancreas can metabolize alcohol both via oxidative and non-oxidative pathways.
The oxidative pathway is catalyzed by the enzyme alcohol dehydrogenase (ADH) and the cytochrome P450 and produces the metabolite acetaldehyde. Finally, the oxidative alcohol metabolism results in the generation of oxygen species (ROS)[84
] and a depletion of the ROS scavenger glutathione[85
]. The increased ROS production (which damage DNA and proteins) and a reduction of proteins that eliminate this ROS (glutathione and enzymes related) lead to oxidant stress and resultant damage in tissue. This stress could be responsible for induce alcoholic pancreatitis as has been demonstrated by several models[86-88
But in pancreas, the non-oxidative pathways may be more important than oxidative metabolism, generating fatty acid ethyl esters (FAEE) by fatty acid ethyl ester synthases (FAEE synthases)[89
]. It has been shown that pancreas exhibits higher FAEE synthase activity than liver[90
] and FAEEs accumulation have been observed in human and rat pancreas after alcohol intake[91-93
The products of alcohol oxidation (acetaldehyde and ROS) and of non-oxidative metabolism have been reported to cause acinar cell injury. Acetaldehyde cause morphological changes in rat and dog’s pancreas[94
] and it has been showed that inhibits CKK-simululated cinar cell secretion[95
]. Also, several studies have demonstrated that alcohol intake causes oxidant stress within the pancreas[86-88
] which may play a role in the alcohol-induced destabilization of zymogen granules and lysosomes. In addition, alcohol oxidation contributes to acinar damage altering the intracellular redox state (a reduced NAD/NADH ratio and increased lactate/piruvate ratio). Other results obtained in isolated mouse pancreatic acinar cells suggest that FAEEs leads to mitochondrial damage, loss of ATP and rise in cytosolic free calcium, which leads to acinar cell toxicity[96
]. Other authors have shown that acute application of ethanol at clinically relevant concentrations (1-50 nmol/L) of isolated acinar cells resulted in calcium influx due to the production of oxidative metabolites of alcohol[97
]. Together, these data show that the role of alcohol metabolites in acinar cell damage could be due to aberrant calcium signals[98
]. FAEEs can elevate Calcium greater that ethanol alone. In addition, FAEEs and their products, fatty acids induces necrosis in acinar cells and this process could be avoided by calcium chelation[99
These physiological changes leads to the pathobiology found in alcoholic pancreatitis including acute and chronic inflammation, elimination of parenchymal cells of the pancreas by a deregulation of apoptosis/necrosis and/or modification in cell proliferation[49
]. The hypothesis called ‘‘necrosis-fibrosis sequence’’ shows these pathological changes where in the early episodes of pancreatitis, patients present focal necrosis and mild fibrosis while patients evaluated years later of the onset of symptoms presents fibrosis and calcifications but not necrosis[100
But the fact that only a minority of heavily drinkers develops pancreatitis or PC indicates that other susceptibility factors as lipid tolerance, smoking or hereditary factors play an important role. In the last decades, genetic susceptibility has been considered between the factors that contribute mainly to the development to alcoholic pancreatic diseases.
One study showed an association between a polymorphism of the gene for one FAEE synthase enzymes, carboxylester lipase and risk of developing alcoholic pancreatitis[101
In addition, the G191R variant in the anionic trypsinogen gene PRSS2
, has been shown to result in a form of trypsin that is easily degraded, is more infrequent in alcoholic pancreatitis patients compared with healthy controls[102
Other studies have demonstrated that mutation N34S in SPINK1
gene is found in 5%-5.8% of patients with pancreatitis compared with 1% in healthy controls[103,104
]. But still the functional consequences of this mutation are unknown.
One of the enzymes that have been also related to alcoholism and drug dependence for decades is ADH. Li et al[105
] performed a recent meta-analyses and confirmed strong associations of the ADH1B
genes with alcoholism and alcohol-related medical diseases[106
]. Recently, Celorrio et al[107
] demonstrated that some specific polymorphism in the genes TH
increase the risk to develop diseases a consequence of excessive consumption of alcohol.
Although it is clear that alcohol consumption is genetically influenced, but characterized by incomplete penetrance, phenocopies, heterogeneity, and polygenic inheritance.
In conclusion, nowadays it appears clear that alcohol consumption is the first or second most common cause of pancreatitis. Based on the different epidemiology studies published in the literature the percentage of pancreatitis cases attributable to alcohol abuse vary since 30% to 90% between countries. A statistical association has been shown with a threshold of ≥ 5 drinks per day with a dose of alcohol ≥ 50 g/d.
But despite that excessive alcohol consumption is primarily responsible for most cases of pancreatitis, alcohol intake alone is not sufficient to lead to this disease, as less than 10% of heavily drinkers develop pancreatitis.
Regarding to PC, the role of alcohol consumption remains less clear, and low to moderate alcohol consumption do not appear to be associated with PC risk, but only chronic heavy drinking increase the risk compared with lightly drinkers.
Genetic variability and environmental exposures such as smoking and diet could act synergistically with regard to pancreatitis and PC and should be considered for further investigations. Probably heavy alcohol consumption may increase pancreatic disease risk most likely potentiating the effects of these other risk factors, but also may have independent genetic and epigenetic effects.