Does Cigarette Smoking Cause Chronic Pancreatitis?

Cigarette smoking is the leading preventable cause of death in the United States, Europe, Japan, and many other affluent nations of the World. The risk for diseases attributed to smoking increases the earlier in life smoking begins and the larger the number of cigarettes smoked. A recent MMWR Morb Mortal Wkly Rep report stated that in the United States in 1996, the incidence of the initiation of cigarette smoking among persons aged 12 to 17 years increased by 30% and that 1,226,000 persons below the age of 18 years are daily smokers. 1 The use of tobacco (smoking and chewing) causes approximately 400,000 deaths. Consequently, state and local health agencies closely monitor tobacco use and its correlates. Current adult cigarette smoking prevalence by state ranged from 13.7% to 30.8%, annual per capita tax paid cigarette sales ranged from 49.1 packs to 186.8 packs, and adult smokeless tobacco use prevalence ranged from 1.4% to 8.8%. 1 The risk for heart attack, cerebrovascular accidents, various cancers of different organs, chronic obstructive pulmonary disease, certain neurologic disorders, and peripheral vascular diseases is markedly enhanced by tobacco use. Although the risk for pancreatic cancer is well correlated with the number of packs of cigarettes/year smoked, 2 it is only recently that various independent observers from the United States and abroad identified cigarette smoking as a factor influencing the incidence, and natural history of chronic pancreatitis (CP). 3–8 Chronic alcoholism has been established as a risk factor for CP, but the added effect of cigarette smoking in the pathogenesis is a novel concept that needs attention. Epidemiologic studies linking cigarette smoking with CP are interesting and convincing. In 1982, Yeo et al. 3 initially reported the possibility that cigarette smoking by chronic alcoholics might enhance the risk for CP. However, cigarette smoking is often an inseparable addiction in most alcoholics. It is difficult to separate the effects of smoking from those of drinking and, hence, not much attention was paid to smoking as a risk factor for CP. In a subsequent study in 1987 conducted among the Native American population in Phoenix, Arizona, we reported a surprisingly low incidence of CP despite a high prevalence of chronic alcoholism and many alcohol-related disorders, such as cirrhosis. 4 Curiously, we understood that the Native Americans had a low incidence of cigarette smoking as a result of a cultural taboo, a factor that we postulated as the reason for the unexpectedly low incidence. 4 In our study, after adjusting for age, we found a strong association between smoking and alcoholic pancreatitis in men but not in women. However, we had only a small number of female patients (alcoholic pancreatitis is predominantly a male disease). Yeo et al. 3 also reported a positive association between smoking and CP in men. Increased smoking was not found in subjects with biliary pancreatitis; gallstones alone are a sufficient cause for acute pancreatitis. A number of studies from Europe subsequently reported a positive correlation between the incidence of CP and heavy cigarette smoking in an alcoholic population. 5–7 In an excellent study from Italy by Talamini et al., 8 reported in this issue, the authors assessed the combined risk of alcoholism and cigarette smoking in the northeastern male Italian population. Male patients with CP in their study drank more than the control subjects and more than the subjects without CP. The percentage of smokers in this group with CP was significantly higher than in the control group and in the group of patients with pancreatic carcinoma but with no history of CP. The authors concluded that alcohol and cigarette smoking are statistically independent risk factors for CP. However, it is important to note that no study has shown that cigarette smoking is an independent risk factor for CP in the absence of chronic alcoholism. The authors examined the effect of alcohol and smoking on pancreatic lithogenesis in 570 consecutive patients and noted that smoking promoted intraductal calculi formation and that, in this regard, alcoholism appeared less important. 9 It is not clear why smoking should promote lithogenesis. Many questions have to be answered. Smoking might increase intraductular protein precipitation, calcium secretion, and/or precipitation of calcium. The pathogenesis of acinar cell injury may be independent and primarily mediated by the effects of alcohol. A hypothetical explanation, which appears to be scientifically plausible, based on experimental and clinical studies has been put forward recently to explain the pathogenesis of CP. The pathogenesis of CP has been attributed to increased free radical production and defective scavenging. Braganza et al. 6 showed that a number of substances (including cigarettes, alcohol, and caffeine) act as xenobiotics. By stimulating the cytochrome P450 system, these substances might increase the production of highly reactive metabolites (free radicals) formed within the tissues. The reaction might be enhanced by alcohol-induced glutathione depletion, which facilitates lipid peroxidation. Cigarette smoking is known to deplete beta carotenes and vitamin C in the body, agents needed to scavenge free radicals. 5 Many antioxidant vitamins and metalloenzymes are nutritional agents that are deficient in most cigarette-smoking persons who are alcoholic. 10 Independent of free radical injury, the toxic effects of nicotine and cigarette smoke on the pancreas have also been carefully estimated in a number of experimental studies, too many to quote here. Cigarette smoke contains a large number of toxins capable of altering acinar cell function. 11 The observed effect of cigarette smoking on alcohol-induced CP serves to explain two other features of the disease. Many recent studies have noted an increased incidence of pancreatic cancer in all forms of CP, alcoholic and nonalcoholic. 2 Cigarette smoking is a definite confounding factor in the case of alcohol-induced CP, because smoking is a known risk factor for pancreatic cancer. 12 The risk for cancer reduces when patients with CP stop smoking. 9 A strong point is made here for including smoking cessation in the management of patients with CP. The current standard of care of alcoholic pancreatitis includes the rehabilitation for alcoholism but not cessation of smoking. Counseling against smoking is politely ignored by physicians, often with the misplaced notion (out of kindness to the patients) that it is not prudent to deprive the patient of two independent pleasures simultaneously. Clinicians have wondered why only a small percentage of alcoholics developed CP. Although there may be many factors (including nutritional, genetic, environmental), it appears that those alcoholics exposed to cigarette smoke are more likely to develop CP than alcoholics who do not smoke. Talamini et al. 8 have provoked our thoughts on the pathogenesis of alcoholic pancreatitis, emphasizing that the effect of smoking on the pancreas needs as much study as the effect of alcohol on the gland, potentially one more nail in the coffin of the tobacco industry.