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Original Investigation |

Alcohol Consumption, Cigarette Smoking, and the Risk of Recurrent Acute and Chronic Pancreatitis FREE

Dhiraj Yadav, MD, MPH; Robert H. Hawes, MD; Randall E. Brand, MD; Michelle A. Anderson, MD; Mary E. Money, MD; Peter A. Banks, MD; Michele D. Bishop, MD; John Baillie, MB, ChB; Stuart Sherman, MD; James DiSario, MD; Frank R. Burton, MD; Timothy B. Gardner, MD; Stephen T. Amann, MD; Andres Gelrud, MD; Christopher Lawrence, MD; Beth Elinoff, RN, MPH; Julia B. Greer, MD, MPH; Michael O’Connell, PhD; M. Michael Barmada, PhD; Adam Slivka, MD, PhD; David C. Whitcomb, MD, PhD; North American Pancreatic Study Group
[+] Author Affiliations

Author Affiliations: Departments of Medicine (Drs Yadav, Greer, O’Connell, Slivka, and Whitcomb and Ms Elinoff) and Human Genetics (Drs Barmada and Whitcomb), University of Pittsburgh, Pittsburgh, Pennsylvania; Digestive Disease Center, Medical University of South Carolina, Charleston (Drs Hawes and Lawrence); Department of Medicine, Evanston Northwestern Healthcare, Chicago, Illinois (Dr Brand); University of Michigan, Ann Arbor (Dr Anderson); Washington County Hospital, Hagerstown, Maryland (Dr Money); Division of Gastroenterology, Brigham and Women's Hospital, Boston, Massachusetts (Dr Banks); Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, Florida (Dr Bishop); Department of Medicine, Duke University Medical Center, Durham, North Carolina (Dr Baillie); Department of Medicine, Indiana University Medical Center, Indianapolis (Dr Sherman); Department of Medicine, University of Utah Health Science Center, Salt Lake City (Dr DiSario); Department of Internal Medicine, St Louis University School of Medicine, St Louis, Missouri (Dr Burton); Dartmouth-Hitchcock Medical Center, Hanover, New Hampshire (Dr Gardner); North Mississippi Medical Center, Tupelo (Dr Amann); and Department of Internal Medicine, University of Cincinnati, Cincinnati, Ohio (Dr Gelrud).Group Information: A list of the North American Pancreatic Study Group investigators was published in Pancreatology (2008;8[4-5]:520-531).


Arch Intern Med. 2009;169(11):1035-1045. doi:10.1001/archinternmed.2009.125.
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Background  Recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP) are associated with alcohol consumption and cigarette smoking. The etiology of RAP and CP is complex, and effects of alcohol and smoking may be limited to specific patient subsets. We examined the current prevalence of alcohol use and smoking and their association with RAP and CP in patients evaluated at US referral centers.

Methods  The North American Pancreatitis Study 2, a multicenter consortium of 20 US centers, prospectively enrolled 540 patients with CP, 460 patients with RAP, and 695 controls from 2000 to 2006. Using self-reported monthly alcohol consumption during the maximum lifetime drinking period, we classified subjects by drinking status: abstainer, light drinker (≤0.5 drink per day), moderate drinker (women, >0.5 to 1 drink per day; men, >0.5 to 2 drinks per day), heavy drinker (women, >1 to <5 drinks per day; men, >2 to <5 drinks per day), or very heavy drinker (≥5 drinks per day for both sexes). Smoking was classified as never, past, or current and was quantified (packs per day and pack-years).

Results  Overall, participants' mean (SD) age was 49.7 (15.4) years; 87.5% were white, and 56.5% were women. Approximately one-fourth of both controls and patients were lifetime abstainers. The prevalence of very heavy drinking among men and women was 38.4% and 11.0% for CP, 16.9% and 5.5% for RAP, and 10.0% and 3.6% for controls. Compared with abstaining and light drinking, very heavy drinking was significantly associated with CP (odds ratio, 3.10; 95% confidence interval, 1.87-5.14) after controlling for age, sex, smoking status, and body mass index. Cigarette smoking was an independent, dose-dependent risk factor for CP and RAP.

Conclusions  Very heavy alcohol consumption and smoking are independent risks for CP. A minority of patients with pancreatitis currently seen at US referral centers report very heavy drinking.

Figures in this Article

Chronic pancreatitis (CP) is an inflammatory syndrome of the pancreas characterized by progressive parenchymal fibrosis, maldigestion, diabetes mellitus, and pain.1 Excessive alcohol consumption has been identified as the primary etiologic factor in numerous studies of adult CP,28 although fewer than 5% of heavy drinkers develop CP.9,10 In 1978, a landmark South African study observed a dose-dependent risk of CP from alcohol consumption.11 However, threshold levels and drinking patterns were not evaluated, and the study only included men. Other studies have suffered from similar limitations.8 Cigarette smoking has been reported to be an independent risk factor for developing CP8,1214 and to increase its rate of progression.15,16 Recently, genetic factors have been identified that also increase the risk of pancreatitis, independent of alcohol consumption or cigarette smoking.1721 To our knowledge, no previous study has evaluated the role of alcohol and smoking in both men and women in recurrent acute pancreatitis (RAP) and CP. Additionally, the current prevalence of alcohol consumption and smoking and their associated risk with RAP and CP in the United States is unknown.

We hypothesized that the etiology of RAP and CP is complex, and that the effects of alcohol and smoking may be limited to specific patient subsets. To further characterize the risk of RAP and CP in US men and women, we prospectively ascertained 1000 patients with pancreatitis and 695 controls from 20 centers with expertise in pancreatic diseases and performed adjusted analyses of alcohol consumption and cigarette smoking.

STUDY POPULATION

The North American Pancreatitis Study 2 (NAPS2)22 prospectively enrolled 1000 affected patients (540 with CP and 460 with RAP) using strict entry criteria and 695 controls from 20 secondary or tertiary pancreatic care centers across the United States between the years 2000 and 2006. Spouses and family members made up 61.7% of controls (34.2% and 27.5%, respectively), while the remaining controls were friends or unrelated to subjects with pancreatitis. A detailed study protocol and methods for the NAPS2 study have been published.22 Recurrent acute pancreatitis was defined by the presence of 2 or more documented episodes of acute pancreatitis, and CP by the presence of changes primarily on imaging studies or histologic specimens. All patients meeting these criteria were eligible for inclusion. Each study center obtained approval from its institutional review board or ethics committee. Informed consent was obtained from all participants prior to their enrollment.

DRINKING CATEGORIES

Study participants completed a questionnaire with assistance from a trained study coordinator that included detailed information on alcohol consumption and smoking. Alcohol questions assessed use in terms of quantity, duration, patterns of use, and relationship with pancreatitis exacerbations as described in detail in an earlier publication.22Ever drinking was defined as a lifetime alcohol intake of more than 20 drinks. We stratified subjects into 5 drinking categories by average reported alcohol consumption in a month during the maximum lifetime drinking period (average number of drinks consumed on a drinking day and number of days per month this amount was consumed) using definitions similar to the National Health Interview Survey (NHIS).23 Drinking categories included abstainers (no alcohol use or <20 drinks in a lifetime), light drinkers (≤0.5 drinks per day or ≤3 drinks per week), moderate drinkers (>0.5 to 1 drink per day or 4 to 7 drinks per week for women; >0.5 to 2 drinks per day or 4 to 14 drinks per week for men), heavy drinkers (>1 to <5 drinks per day or 8 to 34 drinks per week for women; >2 to <5 drinks per day or 15 to 34 drinks per week for men), and very heavy drinkers (≥5 drinks per day or ≥35 drinks per week for both sexes). A drinking category was assigned directly to 1507 subjects (88.9%), while in 141 subjects (8.3%) it was assigned after review of available responses on quantity, frequency, drinking patterns, and responses to TWEAK questions (TWEAK is an adapted acronym for the 5 questions used in the questionnaire: tolerance, worry, eye-opener, amnesia, and “kut” down).22 A drinking category could not be assigned to 47 subjects (2.8%). Information on average daily drinking and duration was used to determine alcohol exposure (in kilograms) during the maximum lifetime drinking period.

DRINKING PATTERNS

As previously described,22 subjects also provided the following information for each drinking phase of their life, beginning with the age of drinking onset: age phase started, pattern of drinking, age pattern changed, and average number of drinks consumed per day during each phase. The drinking patterns were categorized as follows: 1, abstinence; 2, occasional drinking (<15 drinks per month on average and no binges); 3, weekend drinking (≤6 drinks per day for up to 2 days per week); 4, moderate drinking (15 drinks per month up to 2 drinks per d); 5, heavier drinking (>2 drinks per day); and 6, binge drinking (at least 3 days in a row of heavy drinking of >6 drinks per day). The total duration of lifetime alcohol consumption and the proportion of time spent at different drinking levels were calculated using information on drinking patterns and associated ages.

AT-RISK DRINKING

Ever drinkers also completed the TWEAK questionnaire (hold version)24,25 to characterize at-risk drinking habits. Based on the responses, a composite TWEAK score (range, 0-7) was generated for each individual.24 Detailed information on the questions and derivation of the TWEAK score has been published previously.22 A reference period (the months before getting pancreatitis) was used for patients with pancreatitis but not for controls. At-risk drinking was defined as a score of 3 or higher.

CIGARETTE SMOKING

Smoking status was classified as never (smoked <100 cigarettes in lifetime) or ever (smoked >100 cigarettes). Ever smokers were categorized as past or current smokers. Amount of smoking was categorized as less than 1 or 1 or more packs per day (ppd).22 The number of pack-years of smoking was calculated from self-reported amount of smoking (average number of cigarettes smoked per day and the duration of smoking) and stratified as less than 12, 12 to 35, and more than 35 pack-years.

STATISTICAL ANALYSIS

Descriptive analyses are presented as proportions for categorical data and as mean (SD) values or medians and interquartile ranges (IQR) for continuous data. Comparisons of continuous variables between controls and patients with pancreatitis were performed using 1-way analysis of variance and Kruskal-Wallis tests where applicable. If significant results were observed, appropriate 2-group comparisons were performed using the t test or Mann-Whitney test. Categorical data were compared using the χ2 test. The distributions of subjects across drinking categories, amount of smoking, and BMI (≤25, >25 to ≤30, or >30) were compared using the Cochran-Armitage test. The correlation between the drinking categories and TWEAK scores was tested using the Spearman correlation coefficient.

Multivariable logistic regression was used to assess associations of alcohol consumption and cigarette smoking with pancreatitis after controlling for the potential confounding variables of age, sex, and current or maximum body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared). Data were evaluated for colinearity and interactions. For CP, we also performed stratified regression analyses for men and women; abstainers and ever drinkers; never and ever smokers; whites and blacks; and drinking categories. Age was assessed as a continuous variable; all other variables in the models were categorical variables, including alcohol (drinking categories), smoking (never or ever; never, <1, or ≥1 ppd; never, <12, 12-35, or >35 pack-years), BMI (≤25, >25 to ≤30, or >30) and sex. We used abstainers and light drinkers as the reference category for alcohol consumption. Regression models were evaluated by the goodness of fit χ2 test. Two-sided P values less than .05 were considered significant. Data analysis was performed using the R Project software (www.r-project.org) and SPSS version 16 (SPSS Inc, Chicago, Illinois).

Overall, the mean (SD) age for the NAPS222 cohort was 49.7 (15.4) years; 87.5% were white, and 56.5% were women. Controls and patients with CP were older than patients with RAP, and a greater proportion of controls were women (Table 1). Drinking behavior differed by sex and pancreatitis type. Heavy or very heavy drinking was reported by a much greater proportion of patients with CP than controls or patients with RAP. While approximately half of men with CP were heavy or very heavy drinkers, close to two-thirds of women with CP were self-reported abstainers or light drinkers. The demographics and distribution of drinking and smoking categories were generally similar across the top 10 centers that recruited over 80% of all participants.

Table Graphic Jump LocationTable 1. Demographic and Selected Risk Factorsa

Figure 1 illustrates the distribution of drinking categories for controls and patients with pancreatitis. Alcohol exposure (average drinks per day [Figure 2A], duration, and amount of alcohol consumed during the maximum lifetime drinking period) and the proportion of lifetime drinking spent at higher drinking levels (ie, levels 5 or 6) increased from light to very heavy drinkers for both controls and patients with pancreatitis.

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Figure 1.

Distribution of drinking categories among all subjects (A), men only (B), and women only (C). Percentages are based on self-reported alcohol consumption during the maximum lifetime drinking period among controls and patients with recurrent acute pancreatitis (RAP) or chronic pancreatitis (CP). Definitions of drinking categories are detailed in the “Methods” section.

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Figure 2.

Distribution of self-reported alcohol consumption (A) and at-risk drinking behavior (B). Definitions of drinking categories are detailed in the “Methods” section. A, Alcohol consumption (average drinks per day) among controls and patients with recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP) stratified by drinking categories. Data are presented as medians and interquartile ranges (IQR). Error bars represent data falling 1.5 IQR above and below the 25th and 75th percentiles, and open circles represent outliers. B, At-risk drinking behavior (defined as a TWEAK score22 of 3 or higher) among controls and patients with RAP and CP. All subjects with a TWEAK score lower than 3 and subjects who were assigned a drinking category are not shown in the figure.

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Very heavy drinkers formed a distinct subgroup of controls and patients with pancreatitis. Alcohol exposure during the maximum lifetime drinking period in this subgroup was much higher than among the other drinking categories. These individuals also spent a higher proportion of their life engaging in heavier or binge drinking. An overlap for alcohol exposure with very heavy drinkers was observed for 10% to 20% of moderate drinkers and 15% to 30% of heavy drinkers.

Overall, the lifetime drinking duration for controls (median, 29 years; IQR, 17-38) and patients with CP (median, 27; IQR, 17-37) was higher than for patients with RAP (median, 22; IQR, 9-32). Binge drinking during any life period was reported by 4.6% of controls, 7.3% of patients with RAP, and 14.8% of patients with CP who provided responses to questions on drinking categories. Among patients with pancreatitis, most binge drinkers were either heavy drinkers (30% of RAP and 8% of CP) or very heavy drinkers (65% of RAP and 88% of CP). The proportion of time spent binge drinking by very heavy drinkers increased from controls to RAP and CP. At-risk drinking was more common for patients with CP than RAP or controls among both men and women (Table 1). A strong correlation was observed between TWEAK score and drinking categories for the entire cohort (r = 0.69; P < .001) as well as among the individual groups (Figure 2B).

Cigarette smoking was more prevalent among patients with CP than among controls and patients with RAP (Table 1). The prevalence and amount of smoking (Figure 3) increased linearly with the level of drinking in controls and patients with pancreatitis. Almost two-thirds of very heavy drinkers and 51.6% of heavy drinkers with CP reported smoking 1 or more packs per day of cigarettes compared with 13.9% of abstainers and 34.3% of light drinkers. The amount of smoking was significantly higher (among smokers) in patients with CP (26.6 pack-years; IQR, 12.0-46.0) compared with RAP subjects (19.5 pack-years; IQR, 7.9-36.1) (P = .001) and controls (16.2 pack-years; IQR, 6.0-32.7) (P<.001). Patients with CP also had significantly longer smoking duration (median, 30.5 years; IQR, 19.7-39.0) than controls (median, 21.9 years; IQR, 11.4-33.1) (P < .001) and patients with RAP (median, 22.7 years; IQR, 12-32) (P < .001). Duration of smoking for patients with CP was significantly longer than for controls for all drinking categories except abstainers and light drinkers; duration of smoking for patients with CP was also significantly longer than for patients with RAP who were light or heavy drinkers.

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Figure 3.

Distribution of self-reported smoking status (A) and amount (B) stratified by drinking categories. All proportions are based on effective numbers, and never smokers account for the proportions not reflected in the graphs. C indicates control group; CP, chronic pancreatitis group; RAP, recurrent acute pancreatitis group.

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Results for multivariable logistic regression analyses for RAP and CP are summarized in Table 2. In adjusted models, increasing age appeared to have a negative association with RAP (odds ratio [OR] for 10-year increase in age, 0.72; 95% confidence interval [CI], 0.65-0.79) (P < .001) and CP (OR for 10-year increase in age, 0.80; 95% CI, 0.73-0.89) (P < .001). Compared with controls, patients with RAP (OR, 1.61; 95% CI, 1.19-2.18) (P = .002) and CP (OR, 1.53; 95% CI, 1.13-2.07) (P = .01) were more often men. While heavy smoking was positively associated with RAP, alcohol consumption was not associated with RAP at any level.Compared with abstention and light drinking (after we controlled for age, sex, BMI, and smoking), very heavy alcohol consumption was significantly associated with CP (OR, 3.10; 95% CI, 1.87-5.14) (P < .001). The association between smoking and CP was dose-dependent.

Table Graphic Jump LocationTable 2. Multivariable Logistic Regression Analyses Showing Associations of Alcohol Consumption and Smoking With RAP and CPa

Stratified models for CP are summarized in Table 3. Very heavy drinking was significantly associated with CP in men, ever smokers, whites, and blacks. A dose-dependent relationship between smoking and CP was noted for men, women, ever drinkers, and whites. When we tested for interaction between drinking categories and smoking (never/ever or amount), a nonsignificant main effect was seen for the interaction term. However, a trend for interactive relationship between drinking and smoking was observed in stratified models. Among ever smokers, the odds of a patient with CP being a very heavy drinker were almost 5 times greater than the odds of being an abstainer or light drinker (Table 3). In stratified models for drinking categories, after controlling for age, sex, and maximum BMI, we found that the ORs for heavy smoking associated with CP increased with the level of drinking (Table 4). Among heavy or very heavy drinkers, the odds of a patient with CP being a heavy smoker (>35 pack-years) were 13 times greater than those of being a never smoker. A similar observation was noted when smoking was used in the models as ever vs never (data not shown) or as packs per day (Table 4). The trends were stronger for pack-years of smoking than for packs per day, indicating that the duration of smoking is important in addition to the amount of cigarettes smoked per day.

Table Graphic Jump LocationTable 3. Multivariable Logistic Regression Analyses Showing Associations of Alcohol Consumption and Smoking With CP Subjects and Controlsa
Table Graphic Jump LocationTable 4. Multivariable Logistic Regression Findings for the Association of Smoking With CP Stratified by Drinking Categoriesa

To our knowledge, this is the largest US study of risk factors for RAP and CP to date. We observed a smaller than expected relationship of alcohol consumption and pancreatitis and confirmed a significant association of very heavy alcohol consumption and cigarette smoking with CP. Our study is the first to our knowledge to demonstrate that a significant increase in the risk of CP occurs only at or above the threshold of 5 alcoholic drinks per day. Contrary to previous studies,2,48 only 38.4% of men and 11% of women with CP were very heavy drinkers. Although heavy smokers tended to be heavy drinkers, smoking itself was a significant risk factor for pancreatitis.

Accurate quantification of alcohol consumption and its relationship to disease risk is a challenge in any observational study. We used drinking category definitions similar to those used in the NHIS23 US general population survey and the recommendations of other government agencies,26 although we divided the NHIS heavier drinking category into heavy and very heavy to perform more precise comparisons. Self-reported alcohol intake during the maximum lifetime drinking period served as primary data to create drinking categories. This criterion was chosen for subject classification, rather than total lifetime alcohol consumption, to reflect the time of highest alcohol-associated risk. Furthermore, use of lifetime alcohol consumption criteria would classify older individuals with small amounts of daily alcohol consumption over many years in the same risk category as younger individuals who consumed alcohol more heavily for a few years (eg, 100 kg of alcohol can be consumed in 11.6 years at 2 drinks per day or in only 4.6 years at 5 drinks per day).

During the maximum lifetime drinking period, only about one-fourth of patients with CP reported alcohol consumption in amounts typically associated with CP. To avoid underestimating heavy drinking, we analyzed our data using several cutoffs. When we included subjects in the moderate and heavy drinking categories whose alcohol exposure during the maximum lifetime drinking period overlapped with very heavy drinkers, the proportion of very heavy drinkers increased to 9.8% of controls, 13.8% of patients with RAP, and 31.7% of the CP group. Positing a lower threshold for heavy drinking (ie, >14 drinks per week for men and >7 drinks per week for women), we found that the proportion of heavy or very heavy drinkers among patients with CP was 37.9% (50.5% men, 23.9% women). Positing the presence of either an overlap of alcohol exposure during the maximum lifetime drinking period or at-risk or binge drinking, we found that the proportion of very heavy drinkers increased to 17.4% among controls, 21.7% among patients with RAP, and 40.2% (58.3% men, 20.2% women) among participants with CP. Using only average number of drinks on drinking days and omitting frequency increased the proportion of subjects drinking 5 or more drinks on a drinking day to 41.6% (57.2% men, 19.7% women) for patients with CP. However, such criteria classify an infrequent drinker who consumes 5 or more drinks on a drinking day as a very heavy drinker and classifies a large proportion of controls (24.1% overall, 39.1% men and 15.5% women) as very heavy drinkers. Regardless of classification, the proportion of pancreatitis that can be attributed to heavy alcohol intake in our study is much lower than reported in many studies of CP.2,48

Our observation of a lower prevalence of heavy drinking among patients with CP is not completely unexpected. Most of the previous large studies of CP were based on evaluations conducted between 1960 and 1990 (compared with 2000-2006 for NAPS222), when alcohol was the predominant recognized etiologic factor for CP.2,57 Recently, more evidence has been accumulating for other causes of CP, including genetic mutations in PRSS1, CFTR, SPINK1, and chymotrypsin C genes.1721 Therefore, subjects without an obvious cause might be more likely to be referred to expert centers for evaluation (referral bias). Our overall lower rates of heavy drinking may also be attributed to our study's greater proportion of women compared with other studies.2,48 Finally, NAPS222 used imaging evidence on endoscopic retrograde cholangiopancreatography or computed tomography as the primary enrollment criteria. In contrast, many previous studies of CP were conducted prior to routine clinical use of computed tomography or magnetic resonance imaging, when diagnosis relied on less sensitive techniques such as the presence of steatorrhea, diabetes mellitus, and pancreatic calcifications on abdominal radiographs. These features are commonly observed in alcoholic men who are heavy smokers.

We found the threshold drinking amount for association between alcohol use and CP to be 5 or more drinks per day. The wide spectrum of reported smoking and drinking habits in this US population allowed us to evaluate the role of alcohol and smoking in stratified analyses. Although ours is the largest study of its kind to our knowledge, the current study was not adequately powered for analysis of all important subgroups (eg, small proportion of very heavy drinkers among women, very heavy drinkers among nonsmokers, nonsmokers among very heavy drinkers, and a small number of blacks). However, our results point to important trends that should be addressed in future studies. Although there were a limited number of blacks in the NAPS2 study, the previously reported association between alcohol and CP in blacks was confirmed, suggesting racial differences in susceptibility to alcoholic pancreatitis.14,27

Our results confirm the association between smoking and CP8,12,16,28 and demonstrate that this effect is dose dependent. A lack of significance for the interaction term between drinking and smoking is likely owing to coexistent heavy drinking and smoking habits as well as a low prevalence of very heavy drinking among non-smokers and heavy smoking at lower levels of drinking. However, the trend toward synergistic effect of increasing tobacco use plus alcohol use observed in this study was expected based on several observations. In our study, the primary diagnostic criteria for CP was the presence of pancreatic fibrosis. Although the biology of fibrosis is complex, it is now clear that pancreatic stellate cells are responsible for the deposition of most of the extracellular fibrotic proteins, including collagen I and II, fibronectin, and other matrix proteins.2931 Stellate cells are transformed from inactive to active states and proliferate in the context of injury, free radicals, proinflammatory cytokines, and other factors. The deposition of matrix proteins is driven by additional factors, including the anti-inflammatory cytokine transforming growth factor β1 and various growth factors.2932 Both alcohol and components of tobacco (eg, carbon monoxide) are known to have significant effects on the immune system,33,34 but the synergistic mechanisms that lead to fibrosis in CP in humans have not yet been determined. An inverse association was observed between BMI and CP. Plausible hypotheses for this association include weight loss from malabsorption or fear of eating secondary to pain.5,35 In addition, patients with CP were often smokers, and cigarette smoking is associated with lower weight and BMI.36

Potential limitations for the generalizability of our results might include the choice of controls, underreporting of alcohol consumption by study subjects, misclassification of subjects into drinking categories, misclassification of subjects into pack-year categories, higher proportion of women, and participation of expert centers for patient enrollment. The choice of spouses, relatives, or friends as controls who may have shared drinking and smoking habits with affected participants could have introduced a conservative bias and lowered the ORs for alcohol use and smoking with pancreatitis. The prevalence of heavy or very heavy drinkers among controls was higher than in the general population.23 However, this finding was likely owing to our use of a different reference period for creation of drinking categories (maximum lifetime drinking period rather than just the past 12 months).23 Analysis of current drinking in our controls demonstrated that the distribution of heavier drinking was generally similar to the US general population.23

Self-reported alcohol consumption has been shown to be a reliable and valid measure of an individual's alcohol consumption when compared with other measures in research settings (in-person interviews and collateral reports and/or sources).37,38 The validity of drinking category assignments in our study was confirmed by the significant correlation between the drinking categories with self-reported alcohol exposure, drinking patterns, and answers to the TWEAK questionnaire.24,25 The sensitivity of detecting at-risk drinking in patients with CP in our study (using very heavy drinking as the reference) was slightly lower (87%), and the specificity higher (86%), than previously reported results of studies of known alcoholics.24

Although our study included a higher proportion of women (47.6% of CP), 35% of patients in the largest US study on idiopathic and alcoholic CP were women.5 We performed stratified analyses for the prevalence and associations of alcohol and smoking. Therefore, a lower prevalence of very heavy drinking in our cohort cannot be explained solely on the basis of a higher proportion of women in the NAPS2 cohort.22 Our study population was enrolled from secondary and tertiary centers with expertise in pancreatic diseases. A lower proportion of very heavy drinkers and a higher proportion of women in our study highlight the need for future studies to determine the current distribution of demographics and risk factors in the United States at a population level.

While our study confirms very heavy alcohol consumption and cigarette smoking as independent predictors of CP, it also demonstrates that the majority of CP subjects seen at US referral centers are not alcoholics and that many, in fact, are abstainers. Our results indicate that patients with CP can be stratified into 3 distinct categories: (1) those with no or minimal alcohol intake for whom alcohol is unrelated to their disease; (2) very heavy drinkers in whom alcohol and smoking may play a dominant role; and (3) moderate or heavy drinkers where alcohol might be an etiologic cofactor with smoking, other environmental factors, or genetic variables.

In conclusion, only very heavy alcohol consumption and cigarette smoking are significant independent risk factors for CP. Risk for CP from alcohol consumption occurs above a threshold level, while risk due to smoking is dose dependent. Drinking levels in subjects with RAP are similar to controls. Only a minority of patients with RAP and CP currently seen at secondary or tertiary US centers could be categorized as very heavy drinkers.

Correspondence: David C. Whitcomb, MD, PhD, Department of Medicine, University of Pittsburgh, Room 401.4, 3708 Fifth Ave, Pittsburgh, PA 15213 (whitcomb@pitt.edu).

Accepted for Publication: February 14, 2009.

Author Contributions:Study concept and design: Yadav, Bishop, Burton, and Whitcomb. Acquisition of data: Hawes, Brand, Anderson, Money, Banks, Bishop, Baillie, Sherman, DiSario, Burton, Gardner, Amann, Gelrud, Lawrence, Elinoff, O’Connell, Slivka, and Whitcomb. Analysis and interpretation of data: Yadav, Banks, Bishop, Baillie, Sherman, Gardner, Gelrud, Greer, O’Connell, Barmada, and Whitcomb. Drafting of the manuscript: Yadav, Money, Banks, Gelrud, Greer, and Whitcomb. Critical revision of the manuscript for important intellectual content: Hawes, Brand, Anderson, Banks, Bishop, Baillie, Sherman, DiSario, Burton, Gardner, Amann, Gelrud, Lawrence, Elinoff, Greer, O’Connell, Barmada, Slivka, and Whitcomb. Statistical analysis: Yadav, Greer, O’Connell, and Barmada. Obtained funding: Bishop and Whitcomb. Administrative, technical, and material support: Brand, DiSario, Gelrud, Lawrence, Elinoff, O’Connell, Slivka, and Whitcomb. Study supervision: Anderson, Banks, Bishop, Burton, Gelrud, and Whitcomb.

Financial Disclosure: None reported.

Funding/Support: This research was supported by grant DK061451 from the National Institute of Diabetes and Digestive and Kidney Diseases, Rockville, Maryland (Dr Whitcomb); the National Pancreas Foundation, Boston, Massachusetts; and Robert and Vicki Hall, and Andrew and Michelle Aloe.

Previous Presentations: This study was presented at the Digestive Disorders Week; May 17-22, 2008; San Diego, California. An abstract of this article also appeared in Gastroenterology (2008;134[4]:A225).

Additional Contributions: The following physicians and centers also contributed patients to this study: Simon K. Lo, MD, Department of Medicine, Cedars-Sinai Medical Center, University of California, Los Angeles; Mark T. DeMeo, MD, Department of Medicine, Rush University Medical Center, Chicago, Illinois; William M. Steinberg, MD, Washington Hospital Center, Washington, DC; Michael L. Kochman, MD, Department of Medicine, University of Pennsylvania, Philadelphia; Babak Etemad, MD, Department of Gastroenterology and Hepatology, Ochsner Medical Center, New Orleans, Louisiana; and Christopher E. Forsmark, MD, Department of Medicine, University of Florida, Gainesville. Emil Bauer and Pat Schuetz, BS, provided data entry services and data management. Albert B. Lowenfels, MD, reviewed the manuscript and provided helpful comments; Elizabeth D. Kennard, PhD, reviewed the manuscript and the statistical analyses and contributed to the statistical analyses.

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Yadav  DEigenbrodt  MLBriggs  MJWilliams  DKWiseman  EJ Pancreatitis: prevalence and risk factors among male veterans in a detoxification program. Pancreas 2007;34 (4) 390- 398
PubMed
Durbec  JPSarles  H Multicenter survey of the etiology of pancreatic diseases: relationship between the relative risk of developing chronic pancreatitis and alcohol, protein and lipid consumption. Digestion 1978;18 (5-6) 337- 350
PubMed
Bourliere  MBarthet  MBerthezene  PDurbec  JPSarles  H Is tobacco a risk factor for chronic pancreatitis and alcoholic cirrhosis? Gut 1991;32 (11) 1392- 1395
PubMed
Lin  YTamakoshi  AHayakawa  TOgawa  MOhno  YResearch Committee on Intractable Pancreatic Diseases, Associations of alcohol drinking and nutrient intake with chronic pancreatitis: findings from a case-control study in Japan. Am J Gastroenterol 2001;96 (9) 2622- 2627
PubMed
Lowenfels  ABZwemer  FLJhangiani  SPitchumoni  CS Pancreatitis in a native American Indian population. Pancreas 1987;2 (6) 694- 697
PubMed
Maisonneuve  PLowenfels  ABMullhaupt  B  et al.  Cigarette smoking accelerates progression of alcoholic chronic pancreatitis. Gut 2005;54 (4) 510- 514
PubMed
Imoto  MDiMagno  EP Cigarette smoking increases the risk of pancreatic calcification in late-onset but not early-onset idiopathic chronic pancreatitis. Pancreas 2000;21 (2) 115- 119
PubMed
Whitcomb  DCGorry  MCPreston  RA  et al.  Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene. Nat Genet 1996;14 (2) 141- 145
PubMed
Witt  HLuck  WHennies  HC  et al.  Mutations in the gene encoding the serine protease inhibitor, Kazal type 1 are associated with chronic pancreatitis. Nat Genet 2000;25 (2) 213- 216
PubMed
Sharer  NSchwarz  MMalone  G  et al.  Mutations of the cystic fibrosis gene in patients with chronic pancreatitis. N Engl J Med 1998;339 (10) 645- 652
PubMed
Cohn  JAFriedman  KJNoone  PGKnowles  MRSilverman  LMJowell  PS Relation between mutations of the cystic fibrosis gene and idiopathic pancreatitis. N Engl J Med 1998;339 (10) 653- 658
PubMed
Rosendahl  JWitt  HSzmola  R  et al.  Chymotrypsin C (CTRC) variants that diminish activity or secretion are associated with chronic pancreatitis. Nat Genet 2008;40 (1) 78- 82
PubMed
Whitcomb  DCYadav  DSlivka  A  et al. North American Pancreatic Study Group, Multicenter approach to recurrent acute and chronic pancreatitis in the United States: the North American Pancreatitis Study 2 (NAPS2). Pancreatology 2008;8 (4-5) 520- 531
PubMed
National Center of Health Statistics,  Health, United States, 2006.   Hyattsville, MD National Center for Health Statistics2006;
Chan  AWPristach  EAWelte  JWRussell  M Use of the TWEAK test in screening for alcoholism/heavy drinking in three populations. Alcohol Clin Exp Res 1993;17 (6) 1188- 1192
PubMed
Russell  MMartier  SSSokol  RJ  et al.  Screening for pregnancy risk-drinking. Alcohol Clin Exp Res 1994;18 (5) 1156- 1161
PubMed
Dufour  MC What is moderate drinking? defining “drinks” and drinking levels. Alcohol Res Health 1999;23 (1) 5- 14
PubMed
Lowenfels  ABMaisonneuve  PGrover  H  et al.  Racial factors and the risk of chronic pancreatitis. Am J Gastroenterol 1999;94 (3) 790- 794
PubMed
Lin  YTamakoshi  AHayakawa  TOgawa  MOhno  YResearch Committee on Intractable Pancreatic Diseases, Cigarette smoking as a risk factor for chronic pancreatitis: a case-control study in Japan. Pancreas 2000;21 (2) 109- 114
PubMed
Apte  MVPirola  RCWilson  JS Battle-scarred pancreas: role of alcohol and pancreatic stellate cells in pancreatic fibrosis. J Gastroenterol Hepatol 2006;21 ((suppl 3)) S97- S101
PubMed
Bachem  MGZhou  ZZhou  SSiech  M Role of stellate cells in pancreatic fibrogenesis associated with acute and chronic pancreatitis. J Gastroenterol Hepatol 2006;21 ((suppl 3)) S92- S96
PubMed
Omary  MBLugea  ALowe  AWPandol  SJ The pancreatic stellate cell: a star on the rise in pancreatic diseases. J Clin Invest 2007;117 (1) 50- 59
PubMed
Wittel  UAPandey  KKAndrianifahanana  M  et al.  Chronic pancreatic inflammation induced by environmental tobacco smoke inhalation in rats. Am J Gastroenterol 2006;101 (1) 148- 159
PubMed
Hoetzel  ADolinay  TSchmidt  RChoi  AMRyter  SW Carbon monoxide in sepsis. Antioxid Redox Signal 2007;9 (11) 2013- 2026
PubMed
Deng  XWang  LElm  MS  et al.  Chronic alcohol consumption accelerates fibrosis in response to cerulein-induced pancreatitis in rats. Am J Pathol 2005;166 (1) 93- 106
PubMed
Ammann  RWMuellhaupt  B The natural history of pain in alcoholic chronic pancreatitis. Gastroenterology 1999;116 (5) 1132- 1140
PubMed
Rásky  EStronegger  WJFreidl  W The relationship between body weight and patterns of smoking in women and men. Int J Epidemiol 1996;25 (6) 1208- 1212
PubMed
Del Boca  FKDarkes  J The validity of self-reports of alcohol consumption: state of the science and challenges for research. Addiction 2003;98 ((suppl 2)) 1- 12
PubMed
Connors  GJMaisto  SA Drinking reports from collateral individuals. Addiction 2003;98 ((suppl 2)) 21- 29
PubMed

Figures

Place holder to copy figure label and caption
Figure 1.

Distribution of drinking categories among all subjects (A), men only (B), and women only (C). Percentages are based on self-reported alcohol consumption during the maximum lifetime drinking period among controls and patients with recurrent acute pancreatitis (RAP) or chronic pancreatitis (CP). Definitions of drinking categories are detailed in the “Methods” section.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Distribution of self-reported alcohol consumption (A) and at-risk drinking behavior (B). Definitions of drinking categories are detailed in the “Methods” section. A, Alcohol consumption (average drinks per day) among controls and patients with recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP) stratified by drinking categories. Data are presented as medians and interquartile ranges (IQR). Error bars represent data falling 1.5 IQR above and below the 25th and 75th percentiles, and open circles represent outliers. B, At-risk drinking behavior (defined as a TWEAK score22 of 3 or higher) among controls and patients with RAP and CP. All subjects with a TWEAK score lower than 3 and subjects who were assigned a drinking category are not shown in the figure.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Distribution of self-reported smoking status (A) and amount (B) stratified by drinking categories. All proportions are based on effective numbers, and never smokers account for the proportions not reflected in the graphs. C indicates control group; CP, chronic pancreatitis group; RAP, recurrent acute pancreatitis group.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Demographic and Selected Risk Factorsa
Table Graphic Jump LocationTable 2. Multivariable Logistic Regression Analyses Showing Associations of Alcohol Consumption and Smoking With RAP and CPa
Table Graphic Jump LocationTable 3. Multivariable Logistic Regression Analyses Showing Associations of Alcohol Consumption and Smoking With CP Subjects and Controlsa
Table Graphic Jump LocationTable 4. Multivariable Logistic Regression Findings for the Association of Smoking With CP Stratified by Drinking Categoriesa

References

Etemad  BWhitcomb  DC Chronic pancreatitis: diagnosis, classification, and new genetic developments. Gastroenterology 2001;120 (3) 682- 707
PubMed
Ammann  RWAkovbiantz  ALargiader  FSchueler  G Course and outcome of chronic pancreatitis: longitudinal study of a mixed medical-surgical series of 245 patients. Gastroenterology 1984;86 (5, pt 1) 820- 828
PubMed
Andersen  BNPedersen  NTScheel  JWorning  H Incidence of alcoholic chronic pancreatitis in Copenhagen. Scand J Gastroenterol 1982;17 (2) 247- 252
PubMed
Lankisch  PGAssmus  CMaisonneuve  PLowenfels  AB Epidemiology of pancreatic diseases in Luneburg County: a study in a defined German population. Pancreatology 2002;2 (5) 469- 477
PubMed
Layer  PYamamoto  HKalthoff  LClain  JEBakken  LJDiMagno  EP The different courses of early- and late-onset idiopathic and alcoholic chronic pancreatitis. Gastroenterology 1994;107 (5) 1481- 1487
PubMed
Marks  INBank  SLouw  JH Chronic pancreatitis in the Western Cape. Digestion 1973;9 (5) 447- 453
PubMed
Robles-Díaz  GVargas  FUscanga  LFernandez-del Castillo  C Chronic pancreatitis in Mexico City. Pancreas 1990;5 (4) 479- 483
PubMed
Talamini  GBassi  CFalconi  M  et al.  Alcohol and smoking as risk factors in chronic pancreatitis and pancreatic cancer. Dig Dis Sci 1999;44 (7) 1303- 1311
PubMed
Lankisch  PGLowenfels  ABMaisonneuve  P What is the risk of alcoholic pancreatitis in heavy drinkers? Pancreas 2002;25 (4) 411- 412
PubMed
Yadav  DEigenbrodt  MLBriggs  MJWilliams  DKWiseman  EJ Pancreatitis: prevalence and risk factors among male veterans in a detoxification program. Pancreas 2007;34 (4) 390- 398
PubMed
Durbec  JPSarles  H Multicenter survey of the etiology of pancreatic diseases: relationship between the relative risk of developing chronic pancreatitis and alcohol, protein and lipid consumption. Digestion 1978;18 (5-6) 337- 350
PubMed
Bourliere  MBarthet  MBerthezene  PDurbec  JPSarles  H Is tobacco a risk factor for chronic pancreatitis and alcoholic cirrhosis? Gut 1991;32 (11) 1392- 1395
PubMed
Lin  YTamakoshi  AHayakawa  TOgawa  MOhno  YResearch Committee on Intractable Pancreatic Diseases, Associations of alcohol drinking and nutrient intake with chronic pancreatitis: findings from a case-control study in Japan. Am J Gastroenterol 2001;96 (9) 2622- 2627
PubMed
Lowenfels  ABZwemer  FLJhangiani  SPitchumoni  CS Pancreatitis in a native American Indian population. Pancreas 1987;2 (6) 694- 697
PubMed
Maisonneuve  PLowenfels  ABMullhaupt  B  et al.  Cigarette smoking accelerates progression of alcoholic chronic pancreatitis. Gut 2005;54 (4) 510- 514
PubMed
Imoto  MDiMagno  EP Cigarette smoking increases the risk of pancreatic calcification in late-onset but not early-onset idiopathic chronic pancreatitis. Pancreas 2000;21 (2) 115- 119
PubMed
Whitcomb  DCGorry  MCPreston  RA  et al.  Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene. Nat Genet 1996;14 (2) 141- 145
PubMed
Witt  HLuck  WHennies  HC  et al.  Mutations in the gene encoding the serine protease inhibitor, Kazal type 1 are associated with chronic pancreatitis. Nat Genet 2000;25 (2) 213- 216
PubMed
Sharer  NSchwarz  MMalone  G  et al.  Mutations of the cystic fibrosis gene in patients with chronic pancreatitis. N Engl J Med 1998;339 (10) 645- 652
PubMed
Cohn  JAFriedman  KJNoone  PGKnowles  MRSilverman  LMJowell  PS Relation between mutations of the cystic fibrosis gene and idiopathic pancreatitis. N Engl J Med 1998;339 (10) 653- 658
PubMed
Rosendahl  JWitt  HSzmola  R  et al.  Chymotrypsin C (CTRC) variants that diminish activity or secretion are associated with chronic pancreatitis. Nat Genet 2008;40 (1) 78- 82
PubMed
Whitcomb  DCYadav  DSlivka  A  et al. North American Pancreatic Study Group, Multicenter approach to recurrent acute and chronic pancreatitis in the United States: the North American Pancreatitis Study 2 (NAPS2). Pancreatology 2008;8 (4-5) 520- 531
PubMed
National Center of Health Statistics,  Health, United States, 2006.   Hyattsville, MD National Center for Health Statistics2006;
Chan  AWPristach  EAWelte  JWRussell  M Use of the TWEAK test in screening for alcoholism/heavy drinking in three populations. Alcohol Clin Exp Res 1993;17 (6) 1188- 1192
PubMed
Russell  MMartier  SSSokol  RJ  et al.  Screening for pregnancy risk-drinking. Alcohol Clin Exp Res 1994;18 (5) 1156- 1161
PubMed
Dufour  MC What is moderate drinking? defining “drinks” and drinking levels. Alcohol Res Health 1999;23 (1) 5- 14
PubMed
Lowenfels  ABMaisonneuve  PGrover  H  et al.  Racial factors and the risk of chronic pancreatitis. Am J Gastroenterol 1999;94 (3) 790- 794
PubMed
Lin  YTamakoshi  AHayakawa  TOgawa  MOhno  YResearch Committee on Intractable Pancreatic Diseases, Cigarette smoking as a risk factor for chronic pancreatitis: a case-control study in Japan. Pancreas 2000;21 (2) 109- 114
PubMed
Apte  MVPirola  RCWilson  JS Battle-scarred pancreas: role of alcohol and pancreatic stellate cells in pancreatic fibrosis. J Gastroenterol Hepatol 2006;21 ((suppl 3)) S97- S101
PubMed
Bachem  MGZhou  ZZhou  SSiech  M Role of stellate cells in pancreatic fibrogenesis associated with acute and chronic pancreatitis. J Gastroenterol Hepatol 2006;21 ((suppl 3)) S92- S96
PubMed
Omary  MBLugea  ALowe  AWPandol  SJ The pancreatic stellate cell: a star on the rise in pancreatic diseases. J Clin Invest 2007;117 (1) 50- 59
PubMed
Wittel  UAPandey  KKAndrianifahanana  M  et al.  Chronic pancreatic inflammation induced by environmental tobacco smoke inhalation in rats. Am J Gastroenterol 2006;101 (1) 148- 159
PubMed
Hoetzel  ADolinay  TSchmidt  RChoi  AMRyter  SW Carbon monoxide in sepsis. Antioxid Redox Signal 2007;9 (11) 2013- 2026
PubMed
Deng  XWang  LElm  MS  et al.  Chronic alcohol consumption accelerates fibrosis in response to cerulein-induced pancreatitis in rats. Am J Pathol 2005;166 (1) 93- 106
PubMed
Ammann  RWMuellhaupt  B The natural history of pain in alcoholic chronic pancreatitis. Gastroenterology 1999;116 (5) 1132- 1140
PubMed
Rásky  EStronegger  WJFreidl  W The relationship between body weight and patterns of smoking in women and men. Int J Epidemiol 1996;25 (6) 1208- 1212
PubMed
Del Boca  FKDarkes  J The validity of self-reports of alcohol consumption: state of the science and challenges for research. Addiction 2003;98 ((suppl 2)) 1- 12
PubMed
Connors  GJMaisto  SA Drinking reports from collateral individuals. Addiction 2003;98 ((suppl 2)) 21- 29
PubMed

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