Scandinavian Journal of Gastroenterology. 2014; 49: 564–568
ORIGINAL ARTICLE
Low risk of colon cancer in patients with celiac disease
Scand J Gastroenterol Downloaded from informahealthcare.com by Rutgers University on 01/29/15 For personal use only.
UMBERTO VOLTA1, OLIMPIA VINCENTINI2, FEDERICA QUINTARELLI3, CRISTINA FELLI2 & MARCO SILANO2 FOR THE COLLABORATING CENTRES OF THE ITALIAN REGISTRY OF THE COMPLICATIONS OF CELIAC DISEASE 1
Department of Medical and Surgical Sciences/Digestive Diseases and Internal Medicine, St. Orsola-Malpighi Hospital, Bologna, Italy, 2Unit of Human Nutrition and Health, Department of Veterinary Public Health and Food Safety, Istituto Superiore di Sanità, Rome, Italy, and 3Unit of Endocrinology, Department of Medicine of the Systems, S.Eugenio and CTO Alesini Hospital, University of Roma Tor Vergata, Rome, Italy
Abstract Objective. Celiac disease (CD) has strongly been established as associated with some site-specific gastrointestinal malignancies. On the contrary, according to the few reports available, the risk of colon carcinoma in CD patients has been described similar to that of general population. In this cohort study, we describe the risk of colon carcinoma in a group of Italian celiac patients. Materials and methods. The study population included all CD patients diagnosed at the Collaborating Centers of the Italian Registry of CD between 1st January 1982 and 31st December 2006. Upon diagnosis of CD and upon at every subsequent clinical control, the Collaborating Centers filled in a validated form for each CD patient reporting information about demographic data, possible occurrence of a neoplasm and adherence to a gluten-free diet. Results. Out of 1757 celiac patients enrolled, 6 developed a colon carcinoma during the follow-up period (mean: 18.1 years). The standardized incidence ratio (SIR) resulted 0.29 (95% CI = 0.07–0.45). Stratifying the risk for the dietary gluten intake, the SIR dropped to 0.07 (95% CI = 0.009–0.27) for CD patients with a strict adherence to a gluten-free diet. Conclusion. We confirm the previous finding that there is low risk to develop a colon cancer in celiac patients.
Key Words: celiac disease, colon carcinoma, gluten-free diet
Introduction The association between celiac disease (CD) and some site-specific malignancies has been long established. A growing body of seminal studies has been reporting that celiac patients have a higher risk to develop neoplasms of the gastrointestinal (GI) tract, such as enteropathy-associated T-cell lymphoma (EATL), carcinoma of esophagus and small bowel [1–3]. On the contrary, very few epidemiological studies have analyzed the risk estimate of the carcinoma of large intestine among celiac patients. The first report on this topic, back in 2002, described that the frequency of colon carcinoma in a group of celiac patients with iron-deficiency anemia
and/or altered bowel habits was similar to that of general population with these same symptoms [4]. In a population-based celiac cohort, Askling et al. found a slightly increased colon cancer risk (standardized incidence ratio, SIR = 1.9, 95% CI 1.2–2.8), mainly in the ascending and transverse colon [5]. The same paper showed that the risk for colon cancer was not increased in dermatitis herpetiformis, a skin disorder closely related to CD (SIR = 1.0, 95% CI 0.4–1.8). In contrast, other studies estimated a risk for colon cancer in CD equal or even lower to that in general population, risk ranging from 0.85 to 1.1 [6–10]. In this paper, we performed a retrospective analysis of the data collected within the context of the Italian Registry of Complications of CD, aiming at clarifying
Correspondence: Dr. Marco Silano MD, Unit of Human Nutrition and Health, Department of Veterinary Public Health and Food Safety, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Roma, Italy. Tel: +39 06 49906001. Fax: +39 06 49387077. E-mail: [email protected]
(Received 7 November 2013; revised 9 January 2014; accepted 5 February 2014) ISSN 0036-5521 print/ISSN 1502-7708 online 2014 Informa Healthcare DOI: 10.3109/00365521.2014.893012
Colon cancer in celiac disease the risk of colon carcinoma in a cohort of 1757 Italian celiac patients. Methods
Scand J Gastroenterol Downloaded from informahealthcare.com by Rutgers University on 01/29/15 For personal use only.
Study population The study population consists of patients diagnosed with CD at the Collaborating Centers of the Italian Registry of the complication of CD between 1st January 1982 and 31st December 2006. All the diagnosis of CD were revised according to the criteria of the American College of Gastroenterology, including histological evidence of atrophy of small bowel mucosa (degree Marsh 3 or 4) and serological positivity for anti-transglutaminase and/or anti-endomysial antibodies [11]. Criteria for exclusion were the presence of a neoplasm at the diagnosis of CD and irregularities in the collection of data. Collection of data At diagnosis of CD and then upon every clinical control for each CD patient, the Collaborating Centers filled in a validate form with the information about the demographic data (identification code, gender, date of birth), about the CD diagnosis (date of CD diagnosis, symptoms and/or signs prompting the diagnosis of CD, consanguinity), the eventual occurrence of a neoplasm (site, date of diagnosis, symptoms and/or signs prompting the diagnosis of the cancer), the adherence to a gluten-free diet (GFD) and eventually the date and the cause of death. The information about compliance with the gluten-free diet was obtained by interviewing the patients. The population was split into four groups to reflect the degree of exposure to gluten. One group consists of patients who kept a strict adherence to GFD, the second group consists of patients who had up to 4 gluten-containing meals per month, the third group from 5–10 gluten-containing meals per month, and the fourth group who had more than 10 glutencontaining meals per month. The follow-up period was measured from the date at diagnosis of CD to 31st December 2006; patients who died before this date were withdrawn at the date of death. Those lost at follow-up were included up to the date of the last clinical control. All occurring colon carcinoma were noted according to the date of diagnosis and histological diagnosis. Statistical analysis To calculate the expected cases of colon carcinoma, person-years at risk were multiplied by the appropriate
565
gender and 5 years age stratum incidence rates for the Italian population from WHO Globocan 2008 database [12]. The SIR (ratio of the observed to the expected cases) along with the 95% confidence interval, the Student’s t-test and the X2 test were calculated assuming a Poisson distribution of the population. The statistical analysis performed by SPSS software. The collection of data has been approved by Istituto Superiore di Sanità (10959/8916), the data were collected and stored according to national regulation. Results Table I shows the demographic data of the 1757 patients enrolled in the study. Seventy patients were excluded from the study because they developed a cancer before or simultaneously the diagnosis of CD and 138 patients were excluded because of data irregularities (96 were missing of the histological report and 42 of the titer of autoantibodies). The mean duration of follow-up period for each patient was 18.1 years, giving a total of 31,801 person years at risk. The degree of exposure to gluten was expressed dividing our series arbitrarily in four groups, according to the monthly frequency of meals having glutencontaining foods. Most of our patients stated to adhere to a strict GFD (63.4%), the 16.9% of our series used to have from 1 to 4 meals with gluten per month, 9.8% up to 10 meals per month and 9.9% followed an unrestricted diet. Six patients (four females and two males) developed a carcinoma of the large intestine during the follow-up period (Table II). None of them had a history of intestinal polyposis before the diagnosis of CD. The overall SIR (observed cases = 6; expected cases = 28.9) for colon carcinoma resulted 0.29 (95% CI = 0.07–0.45). The cases of colon carcinoma Table I. Demographic characteristics of the 1757 patients enrolled. Characteristic Sex Male Female Age at entry in the study (years) 0–19 20–39 40–59 60 + Mean age at the enrolment (years) ± SD Mean age at the end of follow-up period (years) ± SD Follow-up Years (min–max; mean) Person-years of follow-up
443 (25.2%) 1314 (74.8%) 343 870 403 141 38.6 56.7
(19.5%) (49.5%) (22.9%) (8.1%) ± 12.6 ± 15.8
0–24; 18.1 31,801
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U. Volta et al.
Table II. Characteristic of patients who developed an adenocarcinoma of the large intestine in our cohort. Patient no.
Gender
1* F 2* F 3 M 4* M 5 F 6* F Mean ± SD (years)
Age at diagnosis of CD (years)
Interval between diagnosis of CD and development of neoplasm (years)
Age at development of neoplasm (years)
Adherence to GFD
66.4 60.8 3.1 40.5 52.4 71.8 49.2 ± 25.1
12.4 0.7 15.8 8.0 0.5 2.0 6.6 ± 6.5
78.8 61.5 18.9 48.5 52.9 73.8 55.7 ± 21.5
1 1 4 4 1 1
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Adherence to GFD: 1 = No meals containing gluten; 2 = From 1 to 4 meals containing gluten per month; 3 = From 5 to 10 meals containing gluten per month; 4 = More than 10 meals containing gluten per month. *Patient deceased during the follow-up period.
made within a year from diagnosis of CD are incident cases. Thus, excluding from the analysis these cases in order to avoid the ascertainment bias, the SIR further drops to 0.13 (95% CI = 0.03–0.35). Stratifying the risk for the dietary gluten intake, the SIR further decreases to 0.07 (95% CI = 0.009–0.27) for CD patients who had a strict adherence to a GFD. All the four patients who developed a colon carcinoma despite a good compliance to a GFD were diagnosed with CD at a mean age much higher than that of the cohort of this study (62.8 ± 8.2 vs. 38.6 ± 12.6; Student’s t-test, p < 0.05). Discussion Colon carcinoma is the most frequent malignancy in Italy [12], in the present study CD has not been found associated with this type of cancer. All the previous epidemiological studies, except one reporting a marginal increase of this neoplasm in CD [5], showed a risk estimate ranging from 0.85- to 1.1-fold with respect to matched control populations [6–10]. Here, we report an overall risk as low as 0.29-fold. We attribute this discrepancy in the figures of the risk estimates for colon carcinoma to the different diet composition and genetic background of the population studied. In this paper, we studied a Mediterranean population, while all the other reports on this topic were performed in North European and North American countries [13]. Our finding that CD is not associated with the risk of colon carcinoma is congruent with the results of different analyses of cancer risk in CD. According to these analyses, the risk of some site-specific malignancies in general is elevated in CD, but CD does not have a strong correlation with the overall cancer risk and mortality for neoplasms [3,7,14]. Different causes might account for the overall low risk of colon cancer in CD: the very low gluten load that reaches the large intestine, the different histology of the colon
mucosa with respect to the duodenum, the reduced absorption of fats and carcinogens through the inflamed intestinal mucosa [15]. Very surprisingly, the risk of developing a colon cancer dramatically dropped to an SIR of 0.07 for those patients on a strict GFD. Gluten peptides have been reported to trigger in vitro a proliferative signaling in a cell line derived from a human colon carcinoma, via interleukin 15 – epidermal growth factor cooperative activation [16]. Although also taken together, these data are insufficient to conclude that gluten withdrawal might prevent the in vivo proliferation of normal enterocytes, an early step of the neoplastic cell transformation, this aspect might deserve consideration in further studies. In this context, some confounding factors should be taken in account; celiac patients compliant to a strict GFD are more prone to follow a healthy diet, containing fruits and vegetables [17]. In this regard, it is noteworthy that treated celiac patients are also at low risk of developing breast cancer, which shares with colon cancer some unhealthy dietary habits as causative factor [18,19]. Smoking and a high body mass index (BMI) are also risk factors for colon cancer [15], we do not have data about those habits and this is a limitation of the study. Data from literature reports that CD patients tend to have a lower BMI with respect to healthy counterparts and the percentage of overweight/obese CD patients is significantly lower with respect to the general population [20,21]. Therefore, the low body weight could be a protective factor for celiac patients toward the development of colon cancer. None of our celiac patients who developed a colon cancer had a history of intestinal polyposis, thus confirming the finding by Green et al. that CD is not associated to benign lesion of the colon, as well [22]. In conclusion, this cohort study indicates that celiac patients are at lower risk to develop a colon carcinoma
Colon cancer in celiac disease with respect to the general population. This little risk declines over the first year after the diagnosis of CD and is further lower for treated celiac patients who follow a strict GFD.
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Acknowledgment Source of funding: intramural. Collaborating Centers: Cattedra di Medicina Interna II, Univ. Cattolica, Roma, G.Gasbarrini, M.D., V. De Vitis, M.D.; Dipartimento di Pediatria, Univ. Federico II, Napoli, L. Greco, M.D., S. Auricchio, M.D.; Ospedale per gli infermi di Faenza – Azienda USL di Ravenna, D.Santini, M. D., F. Scaggiante M., M.D., Vincenzi M., Federici M.D.; Istituto Giannina Gaslini, Pediatria III, Genova, E. Castellano, M.D., A.Calvi, M.D.; Cattedra di Gastroenterologia, Dipartimento di Medicina Interna, Univ. Torino, Sategna-Guidetti, S. Grosso; Unità di Gastroenterologia, IRCCS Policlinico S. Matteo, Univ. Pavia, Campanella J., M.D., Corazza G.R., M.D.; Unita’ Operativa di Nutrizione Clinica, Ospedale S. Eugenio, Roma, G. Sandri, M. D., G. Giorgetti, M.D.; Monica Amici, Dipartimento di Medicina Interna, Policlinico S. Orsola-Malpighi, Bologna, U. Volta, M.D., G. Caio; Servizio di Gastroenterologia ed Endoscopia Digestiva, Ospedale USL 9, Treviso, S. Lo Perfido, M.D., ; Divisione di Gastroenterologia, IRCCS Casa Sollievo Sofferenza, San Giovanni Rotondo, Foggia, F. Perri, M.D., V. Festa M.D.,; Clinica di Gastroenterologia ed Epatologia, Univ. Perugia, M.A. Pelli, M.D., M.L. Cavalletti M.D.,; Unità Operativa di Gastroenterologia ed Endoscopia Digestiva, Ospedale di Circolo e Fondazione Macchi, Varese, S. Segato, M.D., M. Curzio M.D.,; Servizio di Gastroenterologia ed Endoscopia Digestiva, Dipartimento Oncologia, Ospedale S. Giovanni AS, Torino, M. Pennazio M. D.,, F.P. Rossini, M.D.; Cattedra di Gastroenterologia, Ist. di Clinica Medica II, Univ. La Sapienza, Roma, A. Picarelli M.D.; Divisione di Gastroenterologia, Ospedale Mauriziano Umberto I, Torino, A. Pera, M.D., E. Ercole M.D.; Unità Operativa di Gastroenterologia, Dip.to di Patofisiologia Clinica, Univ. Pol. “Careggi” Firenze, M.T. Passaleva; Clinica Pediatrica, Servizio di Gastroenterologia, Univ. La Sapienza, Roma, M. Barbato M.D.,; Istituto di Medicina Interna, Univ. Cagliari, P. Usai M.D.,, M.F. Dore M.D.,; Divisione di Gastroenterologia, Ospedale Regionale, Bolzano, F.Chilovi, M.D., L. Piazzi, M.D. L.Zancanella M.D., and Servizio di Gastroenterologia Pediatrica e Servizio di Gastroenterologia, Univ. Modena, V. Boarino, M.D., A. Ferrari M.D.
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Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
References [1] Silano M, Volta U, Vincenzi AD, Dessì M, Vincenzi MD; Collaborating Centers of the Italian Registry of the Complications of Coeliac Disease. Effect of a gluten-free diet on the risk of enteropathy-associated T-cell lymphoma in celiac disease. Dig Dis Sci 2008;53:972–6. [2] Elfström P, Granath F, Ye W, Ludvigsson JF. Low risk of gastrointestinal cancer among patients with celiac disease, inflammation, or latent celiac disease. Clin Gastroenterol Hepatol 2012;10:30–6. [3] Tio M, Cox MR, Eslick GD. Meta-analysis: coeliac disease and the risk of all-cause mortality, any malignancy and lymphoid malignancy. Aliment Pharmacol Ther 2012;35: 540–51. [4] Dickey W. Colon neoplasia co-existing with coeliac disease in older patients: coincidental, probably; important, certainly. Scand J Gastroenterol 2002;37:1054–6. [5] Askling J, Linet M, Gridley G, Halstensen TS, Ekström K, Ekbom A. Cancer incidence in a population-based cohort of individuals hospitalized with celiac disease or dermatitis herpetiformis. Gastroenterology 2002;123:1428–35. [6] Grainge MJ, West J, Solaymani-Dodaran M, Card TR, Logan RF. The long-term risk of malignancy following a diagnosis of coeliac disease or dermatitis herpetiformis: a cohort study. Aliment Pharmacol Ther 2012;35:730–9. [7] Ludvigsson JF. Mortality and malignancy in celiac disease. Gastrointest Endosc Clin N Am 2012;22:705–22. [8] González R, Pereyra L, Mohaidle A Mella JM, Fischer C, Medrano MA, et al. [Celiac disease and risk of colorectal neoplasia]. Acta Gastroenterol Latinoam 2012;42:87–91. [9] Landgren AM, Landgren O, Gridley G, Dores GM, Linet MS, Morton LM. Autoimmune disease and subsequent risk of developing alimentary tract cancers among 4.5 million US male veterans. Cancer 2011;117:1163–71. [10] Freeman HJ Lymphoproliferative and intestinal malignancies in 214 patients with biopsy-defined celiac disease. J Clin Gastroenterol 2004;38:429–34. [11] Rubio-Tapia A, Hill ID, Kelly CP, Calderwood AH, Murray JA; American College of Gastroenterology. ACG clinical guidelines: diagnosis and management of celiac disease. Am J Gastroenterol 2013;108:656–76. [12] WHO. Globocan. 2008. http://globocan.iarc.fr/.Last accessed 16th October 2013. [13] Vergnaud AC, Norat T, Romaguera D, Mouw T, May AM, Romieu I, et al. Fruit and vegetable consumption and prospective weight change in participants of the European Prospective Investigation into Cancer and Nutrition-Physical Activity, Nutrition, Alcohol, Cessation of Smoking, Eating Out of Home, and Obesity study. Am J Clin Nutr 2012;95: 184–93. [14] Godfrey JD, Brantner TL, Brinjikji W Christensen KN, Brogan DL, Van Dyke CT, et al. Morbidity and mortality among older individuals with undiagnosed celiac disease. Gastroenterology 2010;139:763–9. [15] Giovannucci E. Modifiable risk factors for colon cancer. Gastroenterol Clin North Am 2002;31:925–43. [16] Nanayakkara M, Lania G, Maglio M, Discepolo V, Sarno M, Gaito A, et al. An undigested gliadin peptide activates innate
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immunity and proliferative signaling in enterocytes: the role in celiac disease. Am J Clin Nutr 2013;98:1123–35. [17] Freeman HJ. Adult celiac disease and its malignant complications. Gut Liver 2009;3:237–46. [18] Ludvigsson JF, West J, Ekbom A, Stephansson O. Reduced risk of breast, endometrial and ovarian cancer in women with celiac disease. Int J Cancer 2012;131:E244–50. [19] Silano M, Volta U, Mecchia AM, Dessì M, Di Benedetto R, DeVincenziM;CollaboratingcentersoftheItalianregistryofthe complications of coeliac disease. Delayed diagnosis of coeliac disease increases cancer risk. BMC Gastroenterol 2007;7:8.
[20] Kabbani TA, Goldberg A, Kelly CP, Pallav K, Tariq S, et al. Body mass index and the risk of obesity in coeliac disease treated with the gluten-free diet. Aliment Pharmacol Ther 2012;35:723–9. [21] Dall’Asta C, Scarlato AP, Galaverna G, Brighenti F, Pellegrini N. Dietary exposure to fumonisins and evaluation of nutrient intake in a group of adult celiac patients on a gluten-free diet. Mol Nutr Food Res 2012;56:632–40. [22] Lebwohl B, Stavsky E, Neugut AI, Green PH. Risk of colorectal adenomas in patients with coeliac disease. Aliment Pharmacol Ther 2010;32:1037–43.
ORIGINAL ARTICLE
Low risk of colon cancer in patients with celiac disease
Scand J Gastroenterol Downloaded from informahealthcare.com by Rutgers University on 01/29/15 For personal use only.
UMBERTO VOLTA1, OLIMPIA VINCENTINI2, FEDERICA QUINTARELLI3, CRISTINA FELLI2 & MARCO SILANO2 FOR THE COLLABORATING CENTRES OF THE ITALIAN REGISTRY OF THE COMPLICATIONS OF CELIAC DISEASE 1
Department of Medical and Surgical Sciences/Digestive Diseases and Internal Medicine, St. Orsola-Malpighi Hospital, Bologna, Italy, 2Unit of Human Nutrition and Health, Department of Veterinary Public Health and Food Safety, Istituto Superiore di Sanità, Rome, Italy, and 3Unit of Endocrinology, Department of Medicine of the Systems, S.Eugenio and CTO Alesini Hospital, University of Roma Tor Vergata, Rome, Italy
Abstract Objective. Celiac disease (CD) has strongly been established as associated with some site-specific gastrointestinal malignancies. On the contrary, according to the few reports available, the risk of colon carcinoma in CD patients has been described similar to that of general population. In this cohort study, we describe the risk of colon carcinoma in a group of Italian celiac patients. Materials and methods. The study population included all CD patients diagnosed at the Collaborating Centers of the Italian Registry of CD between 1st January 1982 and 31st December 2006. Upon diagnosis of CD and upon at every subsequent clinical control, the Collaborating Centers filled in a validated form for each CD patient reporting information about demographic data, possible occurrence of a neoplasm and adherence to a gluten-free diet. Results. Out of 1757 celiac patients enrolled, 6 developed a colon carcinoma during the follow-up period (mean: 18.1 years). The standardized incidence ratio (SIR) resulted 0.29 (95% CI = 0.07–0.45). Stratifying the risk for the dietary gluten intake, the SIR dropped to 0.07 (95% CI = 0.009–0.27) for CD patients with a strict adherence to a gluten-free diet. Conclusion. We confirm the previous finding that there is low risk to develop a colon cancer in celiac patients.
Key Words: celiac disease, colon carcinoma, gluten-free diet
Introduction The association between celiac disease (CD) and some site-specific malignancies has been long established. A growing body of seminal studies has been reporting that celiac patients have a higher risk to develop neoplasms of the gastrointestinal (GI) tract, such as enteropathy-associated T-cell lymphoma (EATL), carcinoma of esophagus and small bowel [1–3]. On the contrary, very few epidemiological studies have analyzed the risk estimate of the carcinoma of large intestine among celiac patients. The first report on this topic, back in 2002, described that the frequency of colon carcinoma in a group of celiac patients with iron-deficiency anemia
and/or altered bowel habits was similar to that of general population with these same symptoms [4]. In a population-based celiac cohort, Askling et al. found a slightly increased colon cancer risk (standardized incidence ratio, SIR = 1.9, 95% CI 1.2–2.8), mainly in the ascending and transverse colon [5]. The same paper showed that the risk for colon cancer was not increased in dermatitis herpetiformis, a skin disorder closely related to CD (SIR = 1.0, 95% CI 0.4–1.8). In contrast, other studies estimated a risk for colon cancer in CD equal or even lower to that in general population, risk ranging from 0.85 to 1.1 [6–10]. In this paper, we performed a retrospective analysis of the data collected within the context of the Italian Registry of Complications of CD, aiming at clarifying
Correspondence: Dr. Marco Silano MD, Unit of Human Nutrition and Health, Department of Veterinary Public Health and Food Safety, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Roma, Italy. Tel: +39 06 49906001. Fax: +39 06 49387077. E-mail: [email protected]
(Received 7 November 2013; revised 9 January 2014; accepted 5 February 2014) ISSN 0036-5521 print/ISSN 1502-7708 online 2014 Informa Healthcare DOI: 10.3109/00365521.2014.893012
Colon cancer in celiac disease the risk of colon carcinoma in a cohort of 1757 Italian celiac patients. Methods
Scand J Gastroenterol Downloaded from informahealthcare.com by Rutgers University on 01/29/15 For personal use only.
Study population The study population consists of patients diagnosed with CD at the Collaborating Centers of the Italian Registry of the complication of CD between 1st January 1982 and 31st December 2006. All the diagnosis of CD were revised according to the criteria of the American College of Gastroenterology, including histological evidence of atrophy of small bowel mucosa (degree Marsh 3 or 4) and serological positivity for anti-transglutaminase and/or anti-endomysial antibodies [11]. Criteria for exclusion were the presence of a neoplasm at the diagnosis of CD and irregularities in the collection of data. Collection of data At diagnosis of CD and then upon every clinical control for each CD patient, the Collaborating Centers filled in a validate form with the information about the demographic data (identification code, gender, date of birth), about the CD diagnosis (date of CD diagnosis, symptoms and/or signs prompting the diagnosis of CD, consanguinity), the eventual occurrence of a neoplasm (site, date of diagnosis, symptoms and/or signs prompting the diagnosis of the cancer), the adherence to a gluten-free diet (GFD) and eventually the date and the cause of death. The information about compliance with the gluten-free diet was obtained by interviewing the patients. The population was split into four groups to reflect the degree of exposure to gluten. One group consists of patients who kept a strict adherence to GFD, the second group consists of patients who had up to 4 gluten-containing meals per month, the third group from 5–10 gluten-containing meals per month, and the fourth group who had more than 10 glutencontaining meals per month. The follow-up period was measured from the date at diagnosis of CD to 31st December 2006; patients who died before this date were withdrawn at the date of death. Those lost at follow-up were included up to the date of the last clinical control. All occurring colon carcinoma were noted according to the date of diagnosis and histological diagnosis. Statistical analysis To calculate the expected cases of colon carcinoma, person-years at risk were multiplied by the appropriate
565
gender and 5 years age stratum incidence rates for the Italian population from WHO Globocan 2008 database [12]. The SIR (ratio of the observed to the expected cases) along with the 95% confidence interval, the Student’s t-test and the X2 test were calculated assuming a Poisson distribution of the population. The statistical analysis performed by SPSS software. The collection of data has been approved by Istituto Superiore di Sanità (10959/8916), the data were collected and stored according to national regulation. Results Table I shows the demographic data of the 1757 patients enrolled in the study. Seventy patients were excluded from the study because they developed a cancer before or simultaneously the diagnosis of CD and 138 patients were excluded because of data irregularities (96 were missing of the histological report and 42 of the titer of autoantibodies). The mean duration of follow-up period for each patient was 18.1 years, giving a total of 31,801 person years at risk. The degree of exposure to gluten was expressed dividing our series arbitrarily in four groups, according to the monthly frequency of meals having glutencontaining foods. Most of our patients stated to adhere to a strict GFD (63.4%), the 16.9% of our series used to have from 1 to 4 meals with gluten per month, 9.8% up to 10 meals per month and 9.9% followed an unrestricted diet. Six patients (four females and two males) developed a carcinoma of the large intestine during the follow-up period (Table II). None of them had a history of intestinal polyposis before the diagnosis of CD. The overall SIR (observed cases = 6; expected cases = 28.9) for colon carcinoma resulted 0.29 (95% CI = 0.07–0.45). The cases of colon carcinoma Table I. Demographic characteristics of the 1757 patients enrolled. Characteristic Sex Male Female Age at entry in the study (years) 0–19 20–39 40–59 60 + Mean age at the enrolment (years) ± SD Mean age at the end of follow-up period (years) ± SD Follow-up Years (min–max; mean) Person-years of follow-up
443 (25.2%) 1314 (74.8%) 343 870 403 141 38.6 56.7
(19.5%) (49.5%) (22.9%) (8.1%) ± 12.6 ± 15.8
0–24; 18.1 31,801
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Table II. Characteristic of patients who developed an adenocarcinoma of the large intestine in our cohort. Patient no.
Gender
1* F 2* F 3 M 4* M 5 F 6* F Mean ± SD (years)
Age at diagnosis of CD (years)
Interval between diagnosis of CD and development of neoplasm (years)
Age at development of neoplasm (years)
Adherence to GFD
66.4 60.8 3.1 40.5 52.4 71.8 49.2 ± 25.1
12.4 0.7 15.8 8.0 0.5 2.0 6.6 ± 6.5
78.8 61.5 18.9 48.5 52.9 73.8 55.7 ± 21.5
1 1 4 4 1 1
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Adherence to GFD: 1 = No meals containing gluten; 2 = From 1 to 4 meals containing gluten per month; 3 = From 5 to 10 meals containing gluten per month; 4 = More than 10 meals containing gluten per month. *Patient deceased during the follow-up period.
made within a year from diagnosis of CD are incident cases. Thus, excluding from the analysis these cases in order to avoid the ascertainment bias, the SIR further drops to 0.13 (95% CI = 0.03–0.35). Stratifying the risk for the dietary gluten intake, the SIR further decreases to 0.07 (95% CI = 0.009–0.27) for CD patients who had a strict adherence to a GFD. All the four patients who developed a colon carcinoma despite a good compliance to a GFD were diagnosed with CD at a mean age much higher than that of the cohort of this study (62.8 ± 8.2 vs. 38.6 ± 12.6; Student’s t-test, p < 0.05). Discussion Colon carcinoma is the most frequent malignancy in Italy [12], in the present study CD has not been found associated with this type of cancer. All the previous epidemiological studies, except one reporting a marginal increase of this neoplasm in CD [5], showed a risk estimate ranging from 0.85- to 1.1-fold with respect to matched control populations [6–10]. Here, we report an overall risk as low as 0.29-fold. We attribute this discrepancy in the figures of the risk estimates for colon carcinoma to the different diet composition and genetic background of the population studied. In this paper, we studied a Mediterranean population, while all the other reports on this topic were performed in North European and North American countries [13]. Our finding that CD is not associated with the risk of colon carcinoma is congruent with the results of different analyses of cancer risk in CD. According to these analyses, the risk of some site-specific malignancies in general is elevated in CD, but CD does not have a strong correlation with the overall cancer risk and mortality for neoplasms [3,7,14]. Different causes might account for the overall low risk of colon cancer in CD: the very low gluten load that reaches the large intestine, the different histology of the colon
mucosa with respect to the duodenum, the reduced absorption of fats and carcinogens through the inflamed intestinal mucosa [15]. Very surprisingly, the risk of developing a colon cancer dramatically dropped to an SIR of 0.07 for those patients on a strict GFD. Gluten peptides have been reported to trigger in vitro a proliferative signaling in a cell line derived from a human colon carcinoma, via interleukin 15 – epidermal growth factor cooperative activation [16]. Although also taken together, these data are insufficient to conclude that gluten withdrawal might prevent the in vivo proliferation of normal enterocytes, an early step of the neoplastic cell transformation, this aspect might deserve consideration in further studies. In this context, some confounding factors should be taken in account; celiac patients compliant to a strict GFD are more prone to follow a healthy diet, containing fruits and vegetables [17]. In this regard, it is noteworthy that treated celiac patients are also at low risk of developing breast cancer, which shares with colon cancer some unhealthy dietary habits as causative factor [18,19]. Smoking and a high body mass index (BMI) are also risk factors for colon cancer [15], we do not have data about those habits and this is a limitation of the study. Data from literature reports that CD patients tend to have a lower BMI with respect to healthy counterparts and the percentage of overweight/obese CD patients is significantly lower with respect to the general population [20,21]. Therefore, the low body weight could be a protective factor for celiac patients toward the development of colon cancer. None of our celiac patients who developed a colon cancer had a history of intestinal polyposis, thus confirming the finding by Green et al. that CD is not associated to benign lesion of the colon, as well [22]. In conclusion, this cohort study indicates that celiac patients are at lower risk to develop a colon carcinoma
Colon cancer in celiac disease with respect to the general population. This little risk declines over the first year after the diagnosis of CD and is further lower for treated celiac patients who follow a strict GFD.
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Acknowledgment Source of funding: intramural. Collaborating Centers: Cattedra di Medicina Interna II, Univ. Cattolica, Roma, G.Gasbarrini, M.D., V. De Vitis, M.D.; Dipartimento di Pediatria, Univ. Federico II, Napoli, L. Greco, M.D., S. Auricchio, M.D.; Ospedale per gli infermi di Faenza – Azienda USL di Ravenna, D.Santini, M. D., F. Scaggiante M., M.D., Vincenzi M., Federici M.D.; Istituto Giannina Gaslini, Pediatria III, Genova, E. Castellano, M.D., A.Calvi, M.D.; Cattedra di Gastroenterologia, Dipartimento di Medicina Interna, Univ. Torino, Sategna-Guidetti, S. Grosso; Unità di Gastroenterologia, IRCCS Policlinico S. Matteo, Univ. Pavia, Campanella J., M.D., Corazza G.R., M.D.; Unita’ Operativa di Nutrizione Clinica, Ospedale S. Eugenio, Roma, G. Sandri, M. D., G. Giorgetti, M.D.; Monica Amici, Dipartimento di Medicina Interna, Policlinico S. Orsola-Malpighi, Bologna, U. Volta, M.D., G. Caio; Servizio di Gastroenterologia ed Endoscopia Digestiva, Ospedale USL 9, Treviso, S. Lo Perfido, M.D., ; Divisione di Gastroenterologia, IRCCS Casa Sollievo Sofferenza, San Giovanni Rotondo, Foggia, F. Perri, M.D., V. Festa M.D.,; Clinica di Gastroenterologia ed Epatologia, Univ. Perugia, M.A. Pelli, M.D., M.L. Cavalletti M.D.,; Unità Operativa di Gastroenterologia ed Endoscopia Digestiva, Ospedale di Circolo e Fondazione Macchi, Varese, S. Segato, M.D., M. Curzio M.D.,; Servizio di Gastroenterologia ed Endoscopia Digestiva, Dipartimento Oncologia, Ospedale S. Giovanni AS, Torino, M. Pennazio M. D.,, F.P. Rossini, M.D.; Cattedra di Gastroenterologia, Ist. di Clinica Medica II, Univ. La Sapienza, Roma, A. Picarelli M.D.; Divisione di Gastroenterologia, Ospedale Mauriziano Umberto I, Torino, A. Pera, M.D., E. Ercole M.D.; Unità Operativa di Gastroenterologia, Dip.to di Patofisiologia Clinica, Univ. Pol. “Careggi” Firenze, M.T. Passaleva; Clinica Pediatrica, Servizio di Gastroenterologia, Univ. La Sapienza, Roma, M. Barbato M.D.,; Istituto di Medicina Interna, Univ. Cagliari, P. Usai M.D.,, M.F. Dore M.D.,; Divisione di Gastroenterologia, Ospedale Regionale, Bolzano, F.Chilovi, M.D., L. Piazzi, M.D. L.Zancanella M.D., and Servizio di Gastroenterologia Pediatrica e Servizio di Gastroenterologia, Univ. Modena, V. Boarino, M.D., A. Ferrari M.D.
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Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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