See the article "Although alcohol abuse is a major association of chronic pancreatitis, it is well known that only a minority of heavy drinkers develop clinically evident pancreatitis.1,2 This observation has led to a sustained effort to identify factors that may increase the susceptibility of alcoholics to the development and progression of the disease.
One of the candidate susceptibility factors is smoking. The interest in smoking as a risk factor for the development and accelerated progression of alcoholic pancreatitis is understandable given that a number of smoking/nicotine related effects on the pancreas have been described in the literature. High concentrations of nicotine have been shown to increase pancreatic protein synthesis in isolated acini.3 Nicotine has also been shown to induce vacuolisation and nuclear pyknosis in acinar cells.4 Serum levels of pancreatic enzymes are reported to be significantly increased in smokers after intravenous secretin.5–7 In addition, in vivo and in vitro studies have demonstrated that smoking significantly inhibits pancreatic secretion.8,9 The concept that smoking enhances the toxic effects of alcohol on the pancreas was examined in a recent experimental study where cigarette smoke was administered to anaesthetised rats receiving intravenous ethanol; the authors reported that alcohol induced pancreatic ischaemia in rats was significantly potentiated by exposure to cigarette smoke.10
In this issue of Gut, Maisonneuve and colleagues11 have investigated the potential role of smoking in alcoholic pancreatitis using a large cohort (n
=934) of patients with chronic alcoholic pancreatitis (see page 510). The protocol consisted of a retrospective examination of data retrieved from clinical records or computerised databases. Demographic and clinical characteristics were noted as were the date of diagnosis, smoking status, alcohol consumption, and the presence of calcification and/or diabetes at diagnosis. The authors reported that smokers were diagnosed with pancreatitis at a younger age than non-smokers and that the prevalence of calcification at diagnosis was significantly higher in the smoking group. The authors further noted that smoking was significantly associated with the development of calcification after the initial diagnosis of pancreatitis; however, this appeared to be independent of the “smoking dose”, with the risk of developing calcifications being similar in moderate smokers (<1 pack/day) and heavy smokers (>1 pack/day).
=934) of patients with chronic alcoholic pancreatitis (see page 510). The protocol consisted of a retrospective examination of data retrieved from clinical records or computerised databases. Demographic and clinical characteristics were noted as were the date of diagnosis, smoking status, alcohol consumption, and the presence of calcification and/or diabetes at diagnosis. The authors reported that smokers were diagnosed with pancreatitis at a younger age than non-smokers and that the prevalence of calcification at diagnosis was significantly higher in the smoking group. The authors further noted that smoking was significantly associated with the development of calcification after the initial diagnosis of pancreatitis; however, this appeared to be independent of the “smoking dose”, with the risk of developing calcifications being similar in moderate smokers (<1 pack/day) and heavy smokers (>1 pack/day).The observation by Maisonneuve and colleagues11 that alcoholic pancreatitis develops earlier in smokers than in non-smokers is similar to that reported previously by Bourliere and colleagues.12 However, both of these studies have been confounded by the fact that compared with non-smokers, a higher proportion of smokers were also heavy drinkers. Thus the groups being compared were potentially different with respect to two variables, alcohol intake and tobacco consumption. It is notable that when the amount of alcohol consumed in the two groups was controlled for, as in the study of Haber et al in 1993,13 no association was detected between smoking and pancreatitis. This finding highlights a point of critical importance for any studies examining individual susceptibility to alcoholic pancreatitis, that the essential comparison for such studies must be between alcoholics with the disease and alcoholics without the disease so that the index and the control groups differ in only one variable (that is, the presence or absence of pancreatitis). Over the past two decades, a number of candidate susceptibility factors have been examined, including diet, amount and type of alcohol consumed, pattern of alcohol consumption, lipid intolerance (see review by Haber and colleagues14) and smoking.12–15 Inherited factors have also been examined, including blood group antigens, HLA serotypes,16 α1-antitrypsin phenotypes,17 cystic fibrosis genotype,18 tumour necrosis factor α genotype,19 genotypes of alcohol metabolising enzymes (alcohol dehydrogenase (ADH), aldehyde dehydrogenase (ALDH), cytochrome P4502E1 (CYP2E1)20), and mutations of genes related to pancreatic proteins that may play an important role in autodigestive injury to the gland (these include digestive enzymes21–23 and proteins that can inactivate digestive enzymes such as pancreatic secretory trypsin inhibitor (PSTI)).24,25 Not all of the above studies have included alcoholics without pancreatitis as controls and despite the extensive search, a predisposing factor(s) to alcoholic pancreatitis remains to be unequivocally identified.
Maisonneuve and colleagues11 are to be commended for their attempts to address an important question with respect to the pathobiology of alcoholic pancreatitis. The strength of the study lies in the relatively large cohort of subjects involved. However, in addition to the lack of appropriate controls (alcoholics without pancreatitis), the study has a number of limitations (some of which have been acknowledged by the authors themselves) and the findings need to be interpreted with some caution. The retrospective nature of data collection (relying on patient records alone) impacts significantly on the ability to accurately assess alcohol intake or cigarette smoke exposure. In the absence of accurate estimations, the classification of low, moderate, heavy, and very heavy alcohol consumption is somewhat arbitrary. Furthermore, many would argue that those patients consuming less than five drinks per day do not have alcoholic pancreatitis and that alcohol consumption is incidental to another aetiology. Stratification of smokers into less than or more than one pack a day also appears to have no scientific basis. The study is further confounded by inclusion of a relatively large proportion of patients for whom the amount of alcohol consumption and extent of smoking was unknown (27% and 20%, respectively).
It is well established that there is a close correlation between tobacco consumption and alcohol intake26,27 with heavy drinkers often being heavy smokers, and vice versa.28,29 This high prevalence of smoking among alcoholics is a critical issue because unless stringent assessments of drinking and smoking are included in the study protocol, it is difficult to ascertain the relative pathogenic roles of the two factors in tissue injury. In order to conclusively delineate the role of smoking in the initiation or progression of alcohol induced injury, it is important to ensure that lifetime consumption of alcohol and tobacco is accurately measured, preferably in a prospective fashion.