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Coeliac disease and bowel disease: Business association or casual meeting?
Digestive and Liver Disease 42 (2010) 171–172
Contents lists available at ScienceDirect
Digestive and Liver Disease journal homepage: www.elsevier.com/locate/dld
Commentary
Coeliac disease and bowel disease: Business association or casual meeting?夽 Vincenzo Villanacci a,∗ , Gabrio Bassotti b a b
2nd Department of Pathology, Spedali Civili, Brescia, Italy Gastroenterology and Hepatology Section, Department of Clinical and Experimental Medicine, University of Perugia, Italy
1. Coeliac disease and autoimmunity Coeliac disease (CD) is a permanent intolerance to ingested gluten in genetically predisposed individuals presenting HLA DQ2 or DQ8 haplotype, with a prevalence of 1 to 100–200 individuals. The pathophysiological grounds of CD are thought to be of autoimmune origin, and there is ample evidence showing a strong relationship with other autoimmune disorders such as diabetes mellitus type 1, autoimmune thyroiditis and other conditions [1]. Moreover, in recent years case reports and case series have suggested the possibility of an association between CD and inflammatory bowel diseases (IBDs) [2–4]. In this issue of Digestive and Liver Disease [5] Casella et al. assessed the prevalence of CD in a large series of Italian patients with IBD, and found a low (0.5%) result, lower than in the general population; the prevalence of CD was higher in patients with ulcerative colitis than in those with Crohn’s disease. These results differ from those previously reported in a small sample of Italian patients and showing a high incidence of CD in patients with Crohn’s disease, but were consistent with those obtained in a large sample of English patients [4]. Other authors have found higher prevalence [3], but this is likely due to the population selection. 2. Genetics and IBD The possibility of a more than casual association between CD and IBD has been exploited in recent years by trying to identify potential genetic factors predisposing such patients to both diseases. For instance, a major histocompatibility complex class I chain-related gene A (MICA), expressed exclusively on the gastrointestinal epithelium in strong linkage disequilibrium with HLA-DRB1 0301, which in turn is associated with both ulcerative colitis and Crohn’s disease was identified [6], as well as MYO IXB, a gene known to be associated with CD, that was also recently found mutated in IBD patients [7]. Moreover, genetic variation in the chromosome 4q27 region (associated with CD and other autoimmune
夽 Commentary on the article “Prevalence of celiac disease in inflammatory bowel diseases: An IG-IBD multicenter study”. ∗ Corresponding author at: Anatomia Patologica II, Spedali Civili di Brescia, Brescia 25100, Italy. E-mail addresses: [email protected], [email protected] (V. Villanacci).
disorders) predisposes to ulcerative colitis, suggesting a common genetic background for these diseases [8]. However, other wellestablished IBD risk factors were not demonstrated to be candidate genes for CD as well [9]. Thus, actually, a clinical role for HLA typing is suggested for only a few conditions, e.g., celiac disease [10]. Due to the relatively low prevalence of CD in IBD, what is the clinical significance of this association, especially with ulcerative colitis? Since most patients with both conditions often share a long-standing history of iron-deficient anaemia [11], it seems important in patients with IBD (especially ulcerative colitis) with persistent anaemia unresponsive to treatment to look for CD, especially because CD may display a subclinical course for a long period without overt signs of malabsorption [12]. 3. Avoiding pathology overlap Finally, a word of caution on the interpretation of biopsy sample from the upper gut, especially from the duodenum, in IBD patients. Ulcerative colitis is usually confined to the colon and is not present in the small intestine, apart from so-called “backwash ileitis”, limited to the terminal tract of ileum as a reaction to pancolitis, that offers few possibilities of confusion with CD; interestingly however, there are reports of diffuse duodenitis in ulcerative colitis patients that may sometimes be confused with CD [13]. On the other hand, gastroduodenal involvement in Crohn’s disease in referral centres may vary from about 30% to about 80% of patients, and it must sometimes be differentiated from CD [14]. The morphological aspects are fundamental and strictly related to the clinical, instrumental and serological data. Our suggestion, in the duodenum, from a morphological point of view is to adopt a correct methodological approach, i.e. obtaining an adequate number (4–6) of biopsies rather than a single sample [15], correctly oriented on acetate filters and preferentially obtained from areas in the distal and proximal duodenum. More important, in our opinion, is also a precise evaluation of the number of intraepithelial lymphocytes (IELs); a number of IELs over 25/100 epithelial cells with the support of immunostaining for CD3, with or without villous atrophy in the absence of giant cells or granuloma, crypt irregularity and a discontinuous inflammation of the mucosa is particularly suspicious for CD. Multiple sections from each sample should be examined. The ideal number of sections to be examined in routine practice is not established but numbers vary between 2 and 6 .The diag-
1590-8658/$36.00 © 2009 Published by Elsevier Ltd on behalf of Editrice Gastroenterologica Italiana S.r.l. doi:10.1016/j.dld.2009.11.012
172
V. Villanacci, G. Bassotti / Digestive and Liver Disease 42 (2010) 171–172
nostic yield increases when more sections are examined. With this shrewdness a correct differential diagnosis is possible. 4. Take-home messages Casella and colleagues are to be congratulated for providing us with significant data on a large cohort of patients, which help to shed light on the putative relationships between IBD and CD. What conclusions may we infer from this study? First, the prevalence of CD seems to be quite low in Italian IBD patients. Second, as also stated by the authors of this study, these results (in accordance with several other from other countries) do not support routine screening for CD in patients with IBD. A possible exception to this statement is for those IBD subjects with unexplained refractory anaemia, in whom further examinations may sometimes reveal the underlying subclinical CD and, perhaps, patients with ulcerative colitis and persistent diarrhoea notwithstanding treatment, in whom the co-presence of CD (with underlying microscopic colitis) might justify the apparent refractoriness to management. All in all, based on the above considerations, it seems that IBD and CD are to be considered more as simple passing acquaintances than business partners. Conflict of interest None. References [1] Briani C, Samaroo D, Alaedini A. Celiac disease: from gluten to autoimmunity. Autoimmun Rev 2008;7:644–50.
[2] Cottone M, Marrone C, Casà A, et al. Familial occurrence of inflammatory bowel disease in celiac disease. Inflamm Bowel Dis 2003;9:321–3. [3] Yang A, Chen Y, Scherl E, et al. Inflammatory bowel disease in patients with celiac disease. Inflamm Bowel Dis 2005;11:528–32. [4] Leeds JS, Höroldt BS, Sidhu R, et al. Is there an association between coeliac disease and inflammatory bowel diseases? A study of relative prevalence in comparison with population controls. Scand J Gastroenterol 2007;42: 1214–20. [5] Casella G, D’Incà R, Oliva L, et al. Prevalence of celiac disease in inflammatory bowel diseases: an IG-IBD multicentre study. Dig Liver Dis 2010;42: 175–8. [6] Lopez-Vasquez A, Rodrigo L, Fuentes D, et al. MHC class I chain related gene A (MICA) modulates the development of celiac disease in patients with the high risk heterodimer DQA1 0501/DQB1 0201. Gut 2002;50:336–40. [7] Monsuur AJ, de Bakker PI, Alizadeh BZ, et al. Myosin IXB variant increases the risk of celiac disease and points toward a primary intestinal barrier defect. Nat Genet 2005;37:1341–4. [8] Festen EA, Goyette P, Scott R, et al. Genetic variants in the region harbouring IL2/IL21 associated with ulcerative colitis. Gut 2009;58:799–804. [9] Dema B, Fernández-Arquero M, Maluenda C, et al. Lack of association of NKX23, RGM, and ATG16L1 inflammatory bowel disease susceptibility variants with celiac disease I. Hum Immunol 2009;70:946–9. [10] Cassinotti A, Birindelli S, Clerici M, et al. HLA and autoimmune digestive disease: a clinically oriented review for gastroenterologists. Am J Gastroenterol 2009;104:195–217. [11] Hershko C, Skikne B. Pathogenesis and management of iron deficiency anemia: emerging role of celiac disease, Helicobacter pylori, and autoimmune gastritis. Semin Hematol 2009;46:339–50. [12] Armstrong MJ, Robins GG, Howdle PD. Recent advances in coeliac disease. Curr Opin Gastroenterol 2009;25:100–9. [13] Valdez R, Appelman HD, Bronner MP, et al. Diffuse duodenitis associated with ulcerative colitis. Am J Surg Pathol 2000;24:1407–13. [14] Wright CL, Riddell RH. Histology of the stomach and duodenum in Crohn’s disease. Am J Surg Pathol 1998;22:383–90. [15] Pais WP, Duerken DR, Pettigrew NM, et al. How many duodenal biopsy specimens are required to make a diagnosis of celiac disease? Gastrointest Endosc 2008;67:1082–7.
Contents lists available at ScienceDirect
Digestive and Liver Disease journal homepage: www.elsevier.com/locate/dld
Commentary
Coeliac disease and bowel disease: Business association or casual meeting?夽 Vincenzo Villanacci a,∗ , Gabrio Bassotti b a b
2nd Department of Pathology, Spedali Civili, Brescia, Italy Gastroenterology and Hepatology Section, Department of Clinical and Experimental Medicine, University of Perugia, Italy
1. Coeliac disease and autoimmunity Coeliac disease (CD) is a permanent intolerance to ingested gluten in genetically predisposed individuals presenting HLA DQ2 or DQ8 haplotype, with a prevalence of 1 to 100–200 individuals. The pathophysiological grounds of CD are thought to be of autoimmune origin, and there is ample evidence showing a strong relationship with other autoimmune disorders such as diabetes mellitus type 1, autoimmune thyroiditis and other conditions [1]. Moreover, in recent years case reports and case series have suggested the possibility of an association between CD and inflammatory bowel diseases (IBDs) [2–4]. In this issue of Digestive and Liver Disease [5] Casella et al. assessed the prevalence of CD in a large series of Italian patients with IBD, and found a low (0.5%) result, lower than in the general population; the prevalence of CD was higher in patients with ulcerative colitis than in those with Crohn’s disease. These results differ from those previously reported in a small sample of Italian patients and showing a high incidence of CD in patients with Crohn’s disease, but were consistent with those obtained in a large sample of English patients [4]. Other authors have found higher prevalence [3], but this is likely due to the population selection. 2. Genetics and IBD The possibility of a more than casual association between CD and IBD has been exploited in recent years by trying to identify potential genetic factors predisposing such patients to both diseases. For instance, a major histocompatibility complex class I chain-related gene A (MICA), expressed exclusively on the gastrointestinal epithelium in strong linkage disequilibrium with HLA-DRB1 0301, which in turn is associated with both ulcerative colitis and Crohn’s disease was identified [6], as well as MYO IXB, a gene known to be associated with CD, that was also recently found mutated in IBD patients [7]. Moreover, genetic variation in the chromosome 4q27 region (associated with CD and other autoimmune
夽 Commentary on the article “Prevalence of celiac disease in inflammatory bowel diseases: An IG-IBD multicenter study”. ∗ Corresponding author at: Anatomia Patologica II, Spedali Civili di Brescia, Brescia 25100, Italy. E-mail addresses: [email protected], [email protected] (V. Villanacci).
disorders) predisposes to ulcerative colitis, suggesting a common genetic background for these diseases [8]. However, other wellestablished IBD risk factors were not demonstrated to be candidate genes for CD as well [9]. Thus, actually, a clinical role for HLA typing is suggested for only a few conditions, e.g., celiac disease [10]. Due to the relatively low prevalence of CD in IBD, what is the clinical significance of this association, especially with ulcerative colitis? Since most patients with both conditions often share a long-standing history of iron-deficient anaemia [11], it seems important in patients with IBD (especially ulcerative colitis) with persistent anaemia unresponsive to treatment to look for CD, especially because CD may display a subclinical course for a long period without overt signs of malabsorption [12]. 3. Avoiding pathology overlap Finally, a word of caution on the interpretation of biopsy sample from the upper gut, especially from the duodenum, in IBD patients. Ulcerative colitis is usually confined to the colon and is not present in the small intestine, apart from so-called “backwash ileitis”, limited to the terminal tract of ileum as a reaction to pancolitis, that offers few possibilities of confusion with CD; interestingly however, there are reports of diffuse duodenitis in ulcerative colitis patients that may sometimes be confused with CD [13]. On the other hand, gastroduodenal involvement in Crohn’s disease in referral centres may vary from about 30% to about 80% of patients, and it must sometimes be differentiated from CD [14]. The morphological aspects are fundamental and strictly related to the clinical, instrumental and serological data. Our suggestion, in the duodenum, from a morphological point of view is to adopt a correct methodological approach, i.e. obtaining an adequate number (4–6) of biopsies rather than a single sample [15], correctly oriented on acetate filters and preferentially obtained from areas in the distal and proximal duodenum. More important, in our opinion, is also a precise evaluation of the number of intraepithelial lymphocytes (IELs); a number of IELs over 25/100 epithelial cells with the support of immunostaining for CD3, with or without villous atrophy in the absence of giant cells or granuloma, crypt irregularity and a discontinuous inflammation of the mucosa is particularly suspicious for CD. Multiple sections from each sample should be examined. The ideal number of sections to be examined in routine practice is not established but numbers vary between 2 and 6 .The diag-
1590-8658/$36.00 © 2009 Published by Elsevier Ltd on behalf of Editrice Gastroenterologica Italiana S.r.l. doi:10.1016/j.dld.2009.11.012
172
V. Villanacci, G. Bassotti / Digestive and Liver Disease 42 (2010) 171–172
nostic yield increases when more sections are examined. With this shrewdness a correct differential diagnosis is possible. 4. Take-home messages Casella and colleagues are to be congratulated for providing us with significant data on a large cohort of patients, which help to shed light on the putative relationships between IBD and CD. What conclusions may we infer from this study? First, the prevalence of CD seems to be quite low in Italian IBD patients. Second, as also stated by the authors of this study, these results (in accordance with several other from other countries) do not support routine screening for CD in patients with IBD. A possible exception to this statement is for those IBD subjects with unexplained refractory anaemia, in whom further examinations may sometimes reveal the underlying subclinical CD and, perhaps, patients with ulcerative colitis and persistent diarrhoea notwithstanding treatment, in whom the co-presence of CD (with underlying microscopic colitis) might justify the apparent refractoriness to management. All in all, based on the above considerations, it seems that IBD and CD are to be considered more as simple passing acquaintances than business partners. Conflict of interest None. References [1] Briani C, Samaroo D, Alaedini A. Celiac disease: from gluten to autoimmunity. Autoimmun Rev 2008;7:644–50.
[2] Cottone M, Marrone C, Casà A, et al. Familial occurrence of inflammatory bowel disease in celiac disease. Inflamm Bowel Dis 2003;9:321–3. [3] Yang A, Chen Y, Scherl E, et al. Inflammatory bowel disease in patients with celiac disease. Inflamm Bowel Dis 2005;11:528–32. [4] Leeds JS, Höroldt BS, Sidhu R, et al. Is there an association between coeliac disease and inflammatory bowel diseases? A study of relative prevalence in comparison with population controls. Scand J Gastroenterol 2007;42: 1214–20. [5] Casella G, D’Incà R, Oliva L, et al. Prevalence of celiac disease in inflammatory bowel diseases: an IG-IBD multicentre study. Dig Liver Dis 2010;42: 175–8. [6] Lopez-Vasquez A, Rodrigo L, Fuentes D, et al. MHC class I chain related gene A (MICA) modulates the development of celiac disease in patients with the high risk heterodimer DQA1 0501/DQB1 0201. Gut 2002;50:336–40. [7] Monsuur AJ, de Bakker PI, Alizadeh BZ, et al. Myosin IXB variant increases the risk of celiac disease and points toward a primary intestinal barrier defect. Nat Genet 2005;37:1341–4. [8] Festen EA, Goyette P, Scott R, et al. Genetic variants in the region harbouring IL2/IL21 associated with ulcerative colitis. Gut 2009;58:799–804. [9] Dema B, Fernández-Arquero M, Maluenda C, et al. Lack of association of NKX23, RGM, and ATG16L1 inflammatory bowel disease susceptibility variants with celiac disease I. Hum Immunol 2009;70:946–9. [10] Cassinotti A, Birindelli S, Clerici M, et al. HLA and autoimmune digestive disease: a clinically oriented review for gastroenterologists. Am J Gastroenterol 2009;104:195–217. [11] Hershko C, Skikne B. Pathogenesis and management of iron deficiency anemia: emerging role of celiac disease, Helicobacter pylori, and autoimmune gastritis. Semin Hematol 2009;46:339–50. [12] Armstrong MJ, Robins GG, Howdle PD. Recent advances in coeliac disease. Curr Opin Gastroenterol 2009;25:100–9. [13] Valdez R, Appelman HD, Bronner MP, et al. Diffuse duodenitis associated with ulcerative colitis. Am J Surg Pathol 2000;24:1407–13. [14] Wright CL, Riddell RH. Histology of the stomach and duodenum in Crohn’s disease. Am J Surg Pathol 1998;22:383–90. [15] Pais WP, Duerken DR, Pettigrew NM, et al. How many duodenal biopsy specimens are required to make a diagnosis of celiac disease? Gastrointest Endosc 2008;67:1082–7.