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Cigarette smoking and celiac sprue: a case-control study
THE AMERICAN JOURNAL OF GASTROENTEROLOGY © 2001 by Am. Coll. of Gastroenterology Published by Elsevier Science Inc.
Vol. 96, No. 8, 2001 ISSN 0002-9270/01/$20.00 PII S0002-9270(01)02603-X
Cigarette Smoking and Celiac Sprue: A Case-Control Study Anand H. Patel, M.B., B.Ch., Edward V. Loftus, Jr., M.D., Joseph A. Murray, M.D., W. Scott Harmsen, M.S., Alan R. Zinsmeister, Ph.D., and William J. Sandborn, M.D. Department of Internal Medicine, Division of Gastroenterology and Hepatology, and Section of Biostatistics, Mayo Clinic and Foundation, Rochester, Minnesota
OBJECTIVE: Environmental factors other than gliadin exposure and certain HLA haplotypes may play a role in the pathogenesis of celiac disease. Previous studies have suggested a strong inverse relationship between cigarette smoking and celiac disease. We sought to determine the relationship between celiac disease and cigarette smoking in our patient population. METHODS: All newly diagnosed adults with biopsy-proven celiac disease evaluated at Mayo Clinic Rochester between January 1, 1993, and June 30, 1998, were identified. Three clinic patients who were matched to each case on geographical area of residence, age, gender, and calendar year of visit served as controls. Smoking information was obtained from a standard medical questionnaire that was completed by all clinic patients at the time of registration. The adjusted odds ratio for celiac disease in current and former smokers relative to nonsmokers was estimated with a matched three-toone conditional logistic regression model. RESULTS: A total of 82 adults with biopsy-proven celiac disease were identified. At the time of diagnosis, the proportion of current smokers was 10% in cases and 10% in controls, yielding an adjusted odds ratio of 1.5 (95% CI ⫽ 0.5– 4.3). In all, 34% of cases were former smokers versus 28% of controls, yielding an odds ratio of 1.6 (95% CI ⫽ 0.8 –3.2). CONCLUSION: This case-control study was unable to detect an association between cigarette smoking and celiac disease. (Am J Gastroenterol 2001;96:2388 –2391. © 2001 by Am. Coll. of Gastroenterology)
INTRODUCTION Celiac disease is a chronic inflammatory disorder of the small intestine resulting from the ingestion of gluten and related substances found in cereal grains such as wheat, barley, rye, and perhaps oats (1, 2). How gliadin and corresponding prolamins induce small intestinal mucosal inThis work was presented in part at the 64th Annual Scientific Meeting of the American College of Gastroenterology, October 18 –20, 1999, in Phoenix, AZ, and published in abstract form (Am J Gastroenterol 1999;94:2646).
flammation and villous atrophy is unknown, but a number of hypotheses have been advanced. Several lines of evidence strongly suggest that genetic factors play a role. The prevalence of celiac disease among first-degree relatives of patients is between 5% and 20%, and the concordance among identical twins is as high as 75% (3, 4). Certain class II human leukocyte antigen (HLA) haplotypes on chromosome 6, such as DQ2 (DQA1*0501, DQB1*0201), are strongly associated with celiac disease (5). Other factors must also be involved, however, because the aforementioned haplotypes are common, and most individuals with these haplotypes suffer no ill consequences from gluten ingestion. Moreover, there is incomplete concordance of celiac disease among identical twins as well as HLA-identical siblings (4, 6). If gliadin exposure were the only important environmental factor, all susceptible individuals would develop celiac disease immediately after starting a normal diet in infancy or early childhood; in fact, many individuals present with celiac sprue later in life. A case-control study from Dorset, United Kingdom, demonstrated a strong inverse relationship between cigarette smoking and celiac disease, suggesting a protective effect against the development of symptomatic adult onset celiac disease (7). Two other centers from the United Kingdom have published preliminary reports suggesting a similar inverse relationship (8, 9). Cigarette smoking has also been shown to be inversely associated with other inflammatory GI diseases such as ulcerative colitis (10, 11), pouchitis (12), and primary sclerosing cholangitis (13, 14). A positive association between smoking and Crohn’s disease has also been detected (10, 11). Our aim was to determine the prevalence of current, former, and no previous smoking among patients with celiac disease and their age- and sex-matched controls.
MATERIALS AND METHODS Case Selection Our Institutional Review Board approved the study. The Mayo Clinic Rochester pathology index was used to identify potential cases, or patients with well documented, biopsyproven celiac disease. The medical records of patients with
AJG – August, 2001
duodenal or jejunal biopsies showing total or partial villous atrophy who were evaluated between January 1, 1993, and June 30, 1998, were reviewed to determine eligibility. The following information was abstracted from the records: 1) clinical features such as diarrhea, weight loss, steatorrhea, iron deficiency anemia, neuromuscular symptoms, bone disease, and dermatitis herpetiformis; 2) clinical and/or histological improvement after gluten-free diet; and 3) antiendomysial, antigliadin and antireticulin antibody status if performed. Patients who were classified as definite cases were required to have clinical and/or histological improvement with a gluten free diet, or positive serological tests (antiendomysial, antigliadin, or antireticulin antibodies). Although clinical features at presentation were not part of the case definition, the prevalence of various features are provided to demonstrate the broad range of manifestations of celiac disease. Control Selection Mayo Clinic Rochester patients who were matched for age at visit (⫾8 yr), gender, and calendar year of visit (⫾7 yr) served as controls. Controls were also matched on one of five categories of geographical area of residence: Rochester, Minnesota; remainder of southeastern Minnesota; remainder of Minnesota and five surrounding states; and remainder of United States and overseas. A list of potential controls for each case was generated in random order. The potential pool of Mayo Medical Center patients who could serve as controls encompassed the entire medical center (both inpatient and outpatient facilities). Controls were not selected from a particular ward or clinic. Only patients with celiac disease were excluded from the control group. Three matched controls were selected for each case. If a control was ineligible or had no smoking information recorded in the medical history, another control was selected from the list of potential controls. Smoking Information Cigarette smoking information was obtained from a standardized medical questionnaire, which all patients complete at the time of each clinic registration. For cases, smoking information was gathered at the time of first Mayo visit for celiac disease. For controls, similar information was obtained from the Mayo visit closest in time to the matching cases’ first Mayo visit for celiac sprue. Both cases and controls were categorized as current smokers, former smokers, or never smokers at the time of the visit. Current smokers were defined as persons who were actively smoking cigarettes at the time the questionnaire was completed. Former smokers were persons who had previously smoked cigarettes but were not actively smoking at the time of completion of the questionnaire. Never smokers were persons who had not smoked previously and who were not active smokers at the time of visit. The following smoking information was obtained: 1) for all participants, smoking versus nonsmoking history; 2) for
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2389
current smokers, the number of cigarettes and length of time smoked; and 3) for former smokers, the date of stopping smoking, the number of cigarettes, and length of time smoked. Statistical Analysis Demographic characteristics such as age and calendar year of visit were compared between cases and controls using the Wilcoxon rank-sum test. The adjusted odds ratio for celiac sprue and 95% CI as a function of smoking status was based on a matched three-to-one conditional logistic regression model adjusting for possible differences in age and calendar year of visit between cases and controls. The primary analysis was performed on definite cases and their matched controls. The analysis was extended to all patients with villous atrophy of the small intestine and their matched controls.
RESULTS Clinical Characteristics Between January 1, 1993, and June 30, 1998, a total of 105 adult patients with newly diagnosed villous atrophy of the small intestine were seen at Mayo Clinic Rochester. A total of 82 patients (78%) fulfilled our criteria for a definite case of celiac disease. All 82 patients had biopsy-proven total or partial villous atrophy, with clinical and/or histological improvement on a gluten-free diet, and/or with serological tests compatible with celiac disease. The geographical areas of residence of the definite cases were as follows: Rochester, one (1%); remainder of southeastern Minnesota, 13 (16%); remainder of Minnesota and surrounding five states, 35 (43%); remainder of United States and elsewhere, 33 (40%). The median age of diagnosis of celiac disease was 59 yr (range 18 –91 yr), and 58% of patients were women (Table 1). Median follow-up after diagnosis was 10 months (range 0 –74 months). The most common presenting symptoms were diarrhea (75%) and weight loss (74%), but a variety of symptoms and signs were noted (Table 1). By study definition, all patients had histological findings on small bowel biopsies that were compatible with celiac disease. Clinical improvement on a gluten-free diet was noted in all patients with adequate follow-up. Antiendomysial antibodies were present in only 76% of those tested, whereas antigliadin antibodies were present in 83% of those tested (Table 1). Cases and controls were matched exactly with respect to gender and geographical area of residence. The differences between cases and controls with respect to age at first Mayo visit, calendar year of visit, and duration of follow-up were not statistically significant (Table 2). Smoking Data Eight cases (10%) were current smokers at the time of first Mayo visit for celiac disease, versus 24 controls (10%) (Table 3). The crude odds ratio of celiac disease in current smokers relative to never smokers was 1.1 (95% CI ⫽
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Table 1. Demographic and Clinical Characteristics of Celiac Disease Cases Definite Cases Only* (N ⫽ 82) Demographics Median age at diagnosis, yr (range) Females, n (%) Symptoms/findings Diarrhea, n (%) Weight loss, n (%) Neuromuscular symptoms, n (%) Dermatitis herpetiformis, n (%) Iron deficiency anemia, n (%) Bone disease, n (%) Histology Total villous atrophy, n (%) Partial villous atrophy, n (%) Antibodies Antiendomysial, n (%) Antigliadin, n (%) Antireticulin, n (%) Improvement with gluten-free diet Clinical improvement, n (%) Biopsy improvement, n (%)
59 (18–91) 46 (56) 62 (75) 61 (74) 28 (34) 9 (11) 50 (61) 10 (12) 69 (84) 13 (16) 25/33 (76) 10/12 (83) 1/3 (33) 72/72 (100) 10/17 (59)
* Definite cases had total or partial villous atrophy, with either clinical or histological improvement on a gluten-free diet, or positive antiendomysial, antigliadin, or antireticulin antibodies.
0.5–2.6). When adjusted for age and date of visit, the odds ratio of celiac disease in current smokers relative to never smokers was 1.5 (95% CI ⫽ 0.5– 4.3) (Table 3). A total of 28 cases (34%) were former smokers, versus 70 controls (28%) (Table 3). The crude odds ratio of celiac disease in former smokers relative to never smokers was 1.3 (95% CI ⫽ 0.8 –2.3). When adjusted for age and date of visit, the odds ratio of celiac disease in former smokers relative to never smokers was 1.6 (95% CI ⫽ 0.8 –3.2) (Table 3). When the analysis was extended to include all 105 patients with villous atrophy of the small intestine and their controls (not just definite cases and their controls), the results were similar.
DISCUSSION In this case-control study of cigarette smoking habits in patients with celiac disease, we were unable to detect an association between cigarette smoking and celiac sprue. The prevalence of current, former, and never smoking in the cases was not significantly different from the controls. Our
Table 3. Smoking Status in Celiac Disease Cases and Matched Controls, With Odds Ratios (Definite Cases Only*) Smoking Status
Cases (N ⫽ 82)
Controls† (N ⫽ 246)
Odds Ratio‡
95% CI
Never Former Current
46 (56%) 28 (34%) 8 (10%)
152 (62%) 70 (28%) 24 (10%)
1.0 1.6 1.5
0.8–3.2 0.5–4.3
* Definite cases had clinical or histological improvement on a gluten-free diet, or positive antiendomysial, antigliadin, or antireticulin antibodies. † Controls matched on geographical area of residence, age, gender, and calendar year of Mayo Clinic visit. ‡ Odds of having celiac disease relative to never smokers, adjusted for age and date of Mayo Clinic visit.
results contrast with previous studies from the United Kingdom that suggested an inverse relationship similar to that seen in ulcerative colitis (7–9). We could not implicate cigarette smoking as a significant environmental factor in the clinical expression of celiac disease. One of the strengths of our study is that smoking information was obtained in a consistent way from both cases and controls by means of a standardized medical questionnaire that was completed by all clinic patients. Moreover, such information was collected at a point in time close to the diagnosis of celiac disease, rather than years after the fact, so recall bias should be minimized. In a previous study of smoking habits in patients with primary sclerosing cholangitis (11), we found that the results of the same standardized medical questionnaire seemed to be reliable when compared with the results of a questionnaire asking specifically about smoking habits that was mailed directly to study patients years after the diagnosis of sclerosing cholangitis. At the same time, it could be argued that the use of smoking information collected retrospectively may not be as accurate, as patients may be inclined to underreport smoking and other socially relevant habits on a self-completed questionnaire. However, such underreporting should occur in both cases and controls to an equal degree. It is important to note that smoking rates among celiac disease cases were remarkably similar to those seen among cases in two of the previous studies (7, 8). The studies differ mainly in smoking rates among the control groups. The rate of current smoking in our controls was much lower than that in the British studies, whereas the percentage of never smokers was higher. The method of selecting controls differed slightly in that the British study used visitors to an orthopedic/trauma clinic, whereas our controls were selected from patients evaluated in any portion of our medical
Table 2. Comparisons Between Cases and Controls
Age at first Mayo visit (yr) Calendar year of first Mayo visit relative to 1/1/00 (yr) Duration of follow-up (yr) * All values expressed as median (range). † Wilcoxon rank sum test.
Cases* (N ⫽ 82)
Controls* (N ⫽ 246)
p†
59.3 (18.0–91.1) ⫺4.5 (⫺6.8, ⫺1.5)
59.9 (18.2–92.6) ⫺4.6 (⫺8.6, ⫺0.3)
0.71 0.78
0.9 (0–6.1)
0.4 (0–7.5)
0.28
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institution (either outpatient or inpatient). The rate of current smoking in our control group (10%) seemed to be significantly lower than that reported among United States adults in the National Health Interview Survey of 1995 (25%) (15). Conversely, the rate of never smoking in our controls (62%) was higher than that of United States adults in the same survey (52%) (15). Although this may raise questions about the validity of our control group, it is important to note that most of our controls resided in the upper Midwestern portion of the United States. The rates of current smoking in this region in 1998 tended to be lower than the United States as a whole, ranging from 18% in Minnesota and 20% in North Dakota to 27% in South Dakota (16). It is conceivable that the influence of cigarette smoking on adult-onset celiac disease varies according to the prevalence of cigarette smoking among adults, explaining the conflicting results of the two studies. Another important consideration is that the low rate of current smoking in our control group may have contributed to loss of study power, and decreased the chance of detecting a significant association. Additional case-control studies among other populations with different rates of cigarette smoking will be required to resolve the issue.
ADDENDUM Since acceptance of this manuscript, another case-control study of cigarette smoking in celiac disease has been published (Vazquez et al., Am J Gastroenterol 2001;96:798 – 802). This study was performed at a referral center in Argentina (where there is a high prevalence of cigarette smoking), and it suggested an inverse relationship between smoking and celiac disease. Reprint requests and correspondence: Edward V. Loftus, Jr., M.D., Division of Gastroenterology and Hepatology, Mayo Clinic, 200 1st Street, SW, Rochester MN 55905. Received Dec. 5, 2000; accepted Mar. 14, 2001.
REFERENCES 1. Trier JS. Celiac sprue and refractory sprue. In: Feldman M, Scharschmidt BF, Sleisenger MH, Klein S, eds., Sleisenger &
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Fordtran’s gastrointestinal and liver disease, 6th ed. Philadelphia: WB Saunders, 1998:1557–73. Ciclitira PJ. Celiac disease. In: Yamada T, Alpers DH, Laine L, et al, eds. Textbook of gastroenterology, 3rd ed. Philadelphia: Lippincott Williams & Wilkins 1999:1660 –76. Stokes PL, Ferguson R, Holmes GK, et al. Familial aspects of coeliac disease. Q J Med 1976;45:567– 82. Polanco I, Biemond I, van Leeuwen A, et al. Gluten-sensitive enteropathy in Spain. genetic and environmental factors. In: McConnell RB, ed. The genetics of coeliac disease. Lancaster: MTP Press, 1981:211–31. Sollid L, Markussen G, Ek J, et al. Evidence for a primary association of celiac disease to a particular HLA-DQ ␣/ heterodimer. J Exp Med 1989;169:345–50. Marsh MN, Bjarnason I, Shaw J, et al. Studies of intestinal lymphoid tissue. XIV—HLA status, mucosal morphology, permeability and epithelial lymphocyte populations in firstdegree relatives of patients with coeliac disease. Gut 1990;31: 32– 6. Snook JA, Dwyer L, Lee-Elliot C, et al. Adult coeliac disease and cigarette smoking. Gut 1996;39:60 –2. Todi D, Tsai HH. Relationship of coeliac disease to smoking habit and appendicectomy. Gut 1997;41(suppl 3):A217 (abstract). Austin AS, Coupland CA, Thomason K, et al. Is smoking protective in coeliac disease? A population-based study. Gut 1999;44(suppl 1):A74 (abstract). Calkins BM. A meta-analysis of the role of smoking in inflammatory bowel disease. Dig Dis Sci 1989;34:1841–54. Thomas GAO, Rhodes J, Green JT. Inflammatory bowel disease and smoking—a review. Am J Gastroenterol 1998;93: 144 –9. Merrett MN, Mortensen N, Kettlewell M, et al. Smoking may prevent pouchitis in patients with restorative proctocolectomy for ulcerative colitis. Gut 1996;38:362– 4. Loftus EV, Sandborn WJ, Tremaine WJ, et al. Primary sclerosing cholangitis is associated with non-smoking. A casecontrol study. Gastroenterology 1996;110:1496 –502. van Erpecum KJ, Smits SJHM, van de Meeburg PC, et al. Risk of primary sclerosing cholangitis is associated with nonsmoking behavior. Gastroenterology 1996;110:1503– 6. Centers for Disease Control and Prevention. Cigarette smoking among adults—United States, 1995. MMWR 1997;46: 1217–20. Centers for Disease Control and Prevention. State-specific prevalence of current cigarette and cigar smoking among adults—United States, 1998. MMWR 1999;48:1034 –9.
Vol. 96, No. 8, 2001 ISSN 0002-9270/01/$20.00 PII S0002-9270(01)02603-X
Cigarette Smoking and Celiac Sprue: A Case-Control Study Anand H. Patel, M.B., B.Ch., Edward V. Loftus, Jr., M.D., Joseph A. Murray, M.D., W. Scott Harmsen, M.S., Alan R. Zinsmeister, Ph.D., and William J. Sandborn, M.D. Department of Internal Medicine, Division of Gastroenterology and Hepatology, and Section of Biostatistics, Mayo Clinic and Foundation, Rochester, Minnesota
OBJECTIVE: Environmental factors other than gliadin exposure and certain HLA haplotypes may play a role in the pathogenesis of celiac disease. Previous studies have suggested a strong inverse relationship between cigarette smoking and celiac disease. We sought to determine the relationship between celiac disease and cigarette smoking in our patient population. METHODS: All newly diagnosed adults with biopsy-proven celiac disease evaluated at Mayo Clinic Rochester between January 1, 1993, and June 30, 1998, were identified. Three clinic patients who were matched to each case on geographical area of residence, age, gender, and calendar year of visit served as controls. Smoking information was obtained from a standard medical questionnaire that was completed by all clinic patients at the time of registration. The adjusted odds ratio for celiac disease in current and former smokers relative to nonsmokers was estimated with a matched three-toone conditional logistic regression model. RESULTS: A total of 82 adults with biopsy-proven celiac disease were identified. At the time of diagnosis, the proportion of current smokers was 10% in cases and 10% in controls, yielding an adjusted odds ratio of 1.5 (95% CI ⫽ 0.5– 4.3). In all, 34% of cases were former smokers versus 28% of controls, yielding an odds ratio of 1.6 (95% CI ⫽ 0.8 –3.2). CONCLUSION: This case-control study was unable to detect an association between cigarette smoking and celiac disease. (Am J Gastroenterol 2001;96:2388 –2391. © 2001 by Am. Coll. of Gastroenterology)
INTRODUCTION Celiac disease is a chronic inflammatory disorder of the small intestine resulting from the ingestion of gluten and related substances found in cereal grains such as wheat, barley, rye, and perhaps oats (1, 2). How gliadin and corresponding prolamins induce small intestinal mucosal inThis work was presented in part at the 64th Annual Scientific Meeting of the American College of Gastroenterology, October 18 –20, 1999, in Phoenix, AZ, and published in abstract form (Am J Gastroenterol 1999;94:2646).
flammation and villous atrophy is unknown, but a number of hypotheses have been advanced. Several lines of evidence strongly suggest that genetic factors play a role. The prevalence of celiac disease among first-degree relatives of patients is between 5% and 20%, and the concordance among identical twins is as high as 75% (3, 4). Certain class II human leukocyte antigen (HLA) haplotypes on chromosome 6, such as DQ2 (DQA1*0501, DQB1*0201), are strongly associated with celiac disease (5). Other factors must also be involved, however, because the aforementioned haplotypes are common, and most individuals with these haplotypes suffer no ill consequences from gluten ingestion. Moreover, there is incomplete concordance of celiac disease among identical twins as well as HLA-identical siblings (4, 6). If gliadin exposure were the only important environmental factor, all susceptible individuals would develop celiac disease immediately after starting a normal diet in infancy or early childhood; in fact, many individuals present with celiac sprue later in life. A case-control study from Dorset, United Kingdom, demonstrated a strong inverse relationship between cigarette smoking and celiac disease, suggesting a protective effect against the development of symptomatic adult onset celiac disease (7). Two other centers from the United Kingdom have published preliminary reports suggesting a similar inverse relationship (8, 9). Cigarette smoking has also been shown to be inversely associated with other inflammatory GI diseases such as ulcerative colitis (10, 11), pouchitis (12), and primary sclerosing cholangitis (13, 14). A positive association between smoking and Crohn’s disease has also been detected (10, 11). Our aim was to determine the prevalence of current, former, and no previous smoking among patients with celiac disease and their age- and sex-matched controls.
MATERIALS AND METHODS Case Selection Our Institutional Review Board approved the study. The Mayo Clinic Rochester pathology index was used to identify potential cases, or patients with well documented, biopsyproven celiac disease. The medical records of patients with
AJG – August, 2001
duodenal or jejunal biopsies showing total or partial villous atrophy who were evaluated between January 1, 1993, and June 30, 1998, were reviewed to determine eligibility. The following information was abstracted from the records: 1) clinical features such as diarrhea, weight loss, steatorrhea, iron deficiency anemia, neuromuscular symptoms, bone disease, and dermatitis herpetiformis; 2) clinical and/or histological improvement after gluten-free diet; and 3) antiendomysial, antigliadin and antireticulin antibody status if performed. Patients who were classified as definite cases were required to have clinical and/or histological improvement with a gluten free diet, or positive serological tests (antiendomysial, antigliadin, or antireticulin antibodies). Although clinical features at presentation were not part of the case definition, the prevalence of various features are provided to demonstrate the broad range of manifestations of celiac disease. Control Selection Mayo Clinic Rochester patients who were matched for age at visit (⫾8 yr), gender, and calendar year of visit (⫾7 yr) served as controls. Controls were also matched on one of five categories of geographical area of residence: Rochester, Minnesota; remainder of southeastern Minnesota; remainder of Minnesota and five surrounding states; and remainder of United States and overseas. A list of potential controls for each case was generated in random order. The potential pool of Mayo Medical Center patients who could serve as controls encompassed the entire medical center (both inpatient and outpatient facilities). Controls were not selected from a particular ward or clinic. Only patients with celiac disease were excluded from the control group. Three matched controls were selected for each case. If a control was ineligible or had no smoking information recorded in the medical history, another control was selected from the list of potential controls. Smoking Information Cigarette smoking information was obtained from a standardized medical questionnaire, which all patients complete at the time of each clinic registration. For cases, smoking information was gathered at the time of first Mayo visit for celiac disease. For controls, similar information was obtained from the Mayo visit closest in time to the matching cases’ first Mayo visit for celiac sprue. Both cases and controls were categorized as current smokers, former smokers, or never smokers at the time of the visit. Current smokers were defined as persons who were actively smoking cigarettes at the time the questionnaire was completed. Former smokers were persons who had previously smoked cigarettes but were not actively smoking at the time of completion of the questionnaire. Never smokers were persons who had not smoked previously and who were not active smokers at the time of visit. The following smoking information was obtained: 1) for all participants, smoking versus nonsmoking history; 2) for
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current smokers, the number of cigarettes and length of time smoked; and 3) for former smokers, the date of stopping smoking, the number of cigarettes, and length of time smoked. Statistical Analysis Demographic characteristics such as age and calendar year of visit were compared between cases and controls using the Wilcoxon rank-sum test. The adjusted odds ratio for celiac sprue and 95% CI as a function of smoking status was based on a matched three-to-one conditional logistic regression model adjusting for possible differences in age and calendar year of visit between cases and controls. The primary analysis was performed on definite cases and their matched controls. The analysis was extended to all patients with villous atrophy of the small intestine and their matched controls.
RESULTS Clinical Characteristics Between January 1, 1993, and June 30, 1998, a total of 105 adult patients with newly diagnosed villous atrophy of the small intestine were seen at Mayo Clinic Rochester. A total of 82 patients (78%) fulfilled our criteria for a definite case of celiac disease. All 82 patients had biopsy-proven total or partial villous atrophy, with clinical and/or histological improvement on a gluten-free diet, and/or with serological tests compatible with celiac disease. The geographical areas of residence of the definite cases were as follows: Rochester, one (1%); remainder of southeastern Minnesota, 13 (16%); remainder of Minnesota and surrounding five states, 35 (43%); remainder of United States and elsewhere, 33 (40%). The median age of diagnosis of celiac disease was 59 yr (range 18 –91 yr), and 58% of patients were women (Table 1). Median follow-up after diagnosis was 10 months (range 0 –74 months). The most common presenting symptoms were diarrhea (75%) and weight loss (74%), but a variety of symptoms and signs were noted (Table 1). By study definition, all patients had histological findings on small bowel biopsies that were compatible with celiac disease. Clinical improvement on a gluten-free diet was noted in all patients with adequate follow-up. Antiendomysial antibodies were present in only 76% of those tested, whereas antigliadin antibodies were present in 83% of those tested (Table 1). Cases and controls were matched exactly with respect to gender and geographical area of residence. The differences between cases and controls with respect to age at first Mayo visit, calendar year of visit, and duration of follow-up were not statistically significant (Table 2). Smoking Data Eight cases (10%) were current smokers at the time of first Mayo visit for celiac disease, versus 24 controls (10%) (Table 3). The crude odds ratio of celiac disease in current smokers relative to never smokers was 1.1 (95% CI ⫽
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Table 1. Demographic and Clinical Characteristics of Celiac Disease Cases Definite Cases Only* (N ⫽ 82) Demographics Median age at diagnosis, yr (range) Females, n (%) Symptoms/findings Diarrhea, n (%) Weight loss, n (%) Neuromuscular symptoms, n (%) Dermatitis herpetiformis, n (%) Iron deficiency anemia, n (%) Bone disease, n (%) Histology Total villous atrophy, n (%) Partial villous atrophy, n (%) Antibodies Antiendomysial, n (%) Antigliadin, n (%) Antireticulin, n (%) Improvement with gluten-free diet Clinical improvement, n (%) Biopsy improvement, n (%)
59 (18–91) 46 (56) 62 (75) 61 (74) 28 (34) 9 (11) 50 (61) 10 (12) 69 (84) 13 (16) 25/33 (76) 10/12 (83) 1/3 (33) 72/72 (100) 10/17 (59)
* Definite cases had total or partial villous atrophy, with either clinical or histological improvement on a gluten-free diet, or positive antiendomysial, antigliadin, or antireticulin antibodies.
0.5–2.6). When adjusted for age and date of visit, the odds ratio of celiac disease in current smokers relative to never smokers was 1.5 (95% CI ⫽ 0.5– 4.3) (Table 3). A total of 28 cases (34%) were former smokers, versus 70 controls (28%) (Table 3). The crude odds ratio of celiac disease in former smokers relative to never smokers was 1.3 (95% CI ⫽ 0.8 –2.3). When adjusted for age and date of visit, the odds ratio of celiac disease in former smokers relative to never smokers was 1.6 (95% CI ⫽ 0.8 –3.2) (Table 3). When the analysis was extended to include all 105 patients with villous atrophy of the small intestine and their controls (not just definite cases and their controls), the results were similar.
DISCUSSION In this case-control study of cigarette smoking habits in patients with celiac disease, we were unable to detect an association between cigarette smoking and celiac sprue. The prevalence of current, former, and never smoking in the cases was not significantly different from the controls. Our
Table 3. Smoking Status in Celiac Disease Cases and Matched Controls, With Odds Ratios (Definite Cases Only*) Smoking Status
Cases (N ⫽ 82)
Controls† (N ⫽ 246)
Odds Ratio‡
95% CI
Never Former Current
46 (56%) 28 (34%) 8 (10%)
152 (62%) 70 (28%) 24 (10%)
1.0 1.6 1.5
0.8–3.2 0.5–4.3
* Definite cases had clinical or histological improvement on a gluten-free diet, or positive antiendomysial, antigliadin, or antireticulin antibodies. † Controls matched on geographical area of residence, age, gender, and calendar year of Mayo Clinic visit. ‡ Odds of having celiac disease relative to never smokers, adjusted for age and date of Mayo Clinic visit.
results contrast with previous studies from the United Kingdom that suggested an inverse relationship similar to that seen in ulcerative colitis (7–9). We could not implicate cigarette smoking as a significant environmental factor in the clinical expression of celiac disease. One of the strengths of our study is that smoking information was obtained in a consistent way from both cases and controls by means of a standardized medical questionnaire that was completed by all clinic patients. Moreover, such information was collected at a point in time close to the diagnosis of celiac disease, rather than years after the fact, so recall bias should be minimized. In a previous study of smoking habits in patients with primary sclerosing cholangitis (11), we found that the results of the same standardized medical questionnaire seemed to be reliable when compared with the results of a questionnaire asking specifically about smoking habits that was mailed directly to study patients years after the diagnosis of sclerosing cholangitis. At the same time, it could be argued that the use of smoking information collected retrospectively may not be as accurate, as patients may be inclined to underreport smoking and other socially relevant habits on a self-completed questionnaire. However, such underreporting should occur in both cases and controls to an equal degree. It is important to note that smoking rates among celiac disease cases were remarkably similar to those seen among cases in two of the previous studies (7, 8). The studies differ mainly in smoking rates among the control groups. The rate of current smoking in our controls was much lower than that in the British studies, whereas the percentage of never smokers was higher. The method of selecting controls differed slightly in that the British study used visitors to an orthopedic/trauma clinic, whereas our controls were selected from patients evaluated in any portion of our medical
Table 2. Comparisons Between Cases and Controls
Age at first Mayo visit (yr) Calendar year of first Mayo visit relative to 1/1/00 (yr) Duration of follow-up (yr) * All values expressed as median (range). † Wilcoxon rank sum test.
Cases* (N ⫽ 82)
Controls* (N ⫽ 246)
p†
59.3 (18.0–91.1) ⫺4.5 (⫺6.8, ⫺1.5)
59.9 (18.2–92.6) ⫺4.6 (⫺8.6, ⫺0.3)
0.71 0.78
0.9 (0–6.1)
0.4 (0–7.5)
0.28
AJG – August, 2001
institution (either outpatient or inpatient). The rate of current smoking in our control group (10%) seemed to be significantly lower than that reported among United States adults in the National Health Interview Survey of 1995 (25%) (15). Conversely, the rate of never smoking in our controls (62%) was higher than that of United States adults in the same survey (52%) (15). Although this may raise questions about the validity of our control group, it is important to note that most of our controls resided in the upper Midwestern portion of the United States. The rates of current smoking in this region in 1998 tended to be lower than the United States as a whole, ranging from 18% in Minnesota and 20% in North Dakota to 27% in South Dakota (16). It is conceivable that the influence of cigarette smoking on adult-onset celiac disease varies according to the prevalence of cigarette smoking among adults, explaining the conflicting results of the two studies. Another important consideration is that the low rate of current smoking in our control group may have contributed to loss of study power, and decreased the chance of detecting a significant association. Additional case-control studies among other populations with different rates of cigarette smoking will be required to resolve the issue.
ADDENDUM Since acceptance of this manuscript, another case-control study of cigarette smoking in celiac disease has been published (Vazquez et al., Am J Gastroenterol 2001;96:798 – 802). This study was performed at a referral center in Argentina (where there is a high prevalence of cigarette smoking), and it suggested an inverse relationship between smoking and celiac disease. Reprint requests and correspondence: Edward V. Loftus, Jr., M.D., Division of Gastroenterology and Hepatology, Mayo Clinic, 200 1st Street, SW, Rochester MN 55905. Received Dec. 5, 2000; accepted Mar. 14, 2001.
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