- Email: [email protected]
Diagnosing coeliac disease: Is the videocapsule a suitable tool?
A.D. Hopper et al. / Digestive and Liver Disease 39 (2007) 140–145 [26] Health Do. National Schedule of Reference Costs—NHS Trusts Day Cases HRG Data. http://www.dh.gov.uk/assetRoot/04/13/32/25/ 04133225.xls 2006: Appendix NSRC1C. [27] Thijs WJ, van Baarlen J, Kleibeuker JH, Kolkman JJ. Duodenal versus jejunal biopsies in suspected celiac disease. Endoscopy 2004;36:993–6. [28] Gasbarrini A, Ojetti V, Cuoco L, Cammarota G, Migneco A, Armuzzi A, et al. Lack of endoscopic visualization of intestinal villi with the “immersion technique” in overt atrophic celiac disease. Gastrointest Endosc 2003;57:348–51. [29] Cammarota G, Martino A, Pirozzi GA, Cianci R, Cremonini F, Zuccala G, et al. Direct visualization of intestinal villi by high-resolution magnifying upper endoscopy: a validation study. Gastrointest Endosc 2004;60:732–8. [30] Siegel LM, Stevens PD, Lightdale CJ, Green PH, Goodman S, Garcia-Carrasquillo RJ, et al. Combined magnification endoscopy with chromoendoscopy in the evaluation of patients with suspected malabsorption. Gastrointest Endosc 1997;46:226–30.
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[31] Badreldin R, Barrett P, Wooff DA, Mansfield J, Yiannakou Y. How good is zoom endoscopy for assessment of villous atrophy in coeliac disease? Endoscopy 2005;37:994–8. [32] Sanders DS, Carter MJ, Hurlstone DP, Pearce A, Ward AM, McAlindon ME, et al. Association of adult coeliac disease with irritable bowel syndrome: a case-control study in patients fulfilling ROME II criteria referred to secondary care. Lancet 2001;358:1504–8. [33] Horoldt BS, McAlindon ME, Stephenson TJ, Hadjivassiliou M, Sanders DS. Making the diagnosis of coeliac disease: is there a role for push enteroscopy? Eur J Gastroenterol Hepatol 2004;16: 1143–6. [34] Wahab PJ, Crusius JB, Meijer JW, Mulder CJ. Gluten challenge in borderline gluten-sensitive enteropathy. Am J Gastroenterol 2001;96:1464–9. [35] Tursi A, Brandimarte G. The symptomatic and histologic response to a gluten-free diet in patients with borderline enteropathy. J Clin Gastroenterol 2003;36:13–7.
Commentary
Diagnosing coeliac disease: Is the videocapsule a suitable tool? E. Rondonotti, R. de Franchis ∗ Department of Medical Sciences, University of Milan and Gastroenterology and GI Endoscopy Unit, Ospedale Maggiore Policlinico, Mangiagalli and Regina Elena Foundation, Milan, Italy Available online 14 December 2006
In Western countries, coeliac disease (CD) has an estimated incidence of 2–13 cases/100,000 people per year [1,2] and a prevalence of 0.7–2% [3]. CD is characterised by intolerance to gluten: in genetically predisposed subjects, ingestion of gluten results in small intestinal mucosal inflammation and damage [4]. Such damage ranges from mild – with an increase in the number of intraepithelial lymphocytes and crypt hyperplasia – to severe, with various degrees of villous atrophy [5,6]. The most typical clinical manifestations of CD are abdominal symptoms, diarrhoea, growth failure and malabsorption of various nutrients. Atypical manifestations such as endocrine dysfunction, anaemia, liver function abnormalities, osteoporosis, infertility, cerebellar ataxia, dermatitis herpetiformis, and alopecia may also occur. However, the symptoms are often vague or subclinical, whereas about 10% of diagnosed patients are totally asymptomatic [3,7]. It is estimated that, for every case of CD identified, 3–7 remain undiagnosed [3]. Classically, the finding of small bowel villous atrophy on duodenal biopsy is the mainstay of diagnosis. Nowadays, serological testing for anti-endomysial (EMA) and antitissue transglutaminase (anti-tTG) antibodies has become the initial diagnostic test in subjects with suspected CD, ∗ Corresponding author. Tel.: +39 02 5503 5331/2; fax: +39 02 5032 0747.
E-mail address: [email protected] (R. de Franchis)
since these antibodies have combined positive and negative predictive values in excess of 90%. Therefore, the current diagnostic algorithm for patients with suspected coeliac disease includes serological testing for EMA and/or anti-tTG followed by upper GI endoscopy with multiple duodenal biopsies. However, duodenal biopsy is not ideal as the gold standard for the diagnosis of CD: obtaining adequate and properly oriented tissue samples may be difficult, mucosal lesions may be patchy and thus missed by the biopsy, and, in some cases, the most severe mucosal changes occur in the jejunum, which is not accessible to conventional upper GI endoscopy [3]. In addition, endoscopy is perceived as unpleasant by some patients, and this limits its use, especially by asymptomatic subjects. As a result, a proportion of potential candidates for duodenal biopsy choose to defer the procedure. Over the last 6 years, videocapsule endoscopy (VCE) has become an important diagnostic tool for the evaluation of the small intestine, since it has been shown to be superior to other diagnostic tools for the diagnosis of a variety of small bowel diseases, including refractory CD [8]. VCE produces high quality images of the small bowel mucosa, with an eight-fold magnification and is able to detect minute mucosal details, including changes in intestinal villi. For these reasons VCE may be a useful tool for the diagnosis of CD; indeed, in a pilot study on VCE in 10 patients with untreated CD, the characteristic villous atrophy was apparent in all patients [9]. The
146
E. Rondonotti, R. de Franchis / Digestive and Liver Disease 39 (2007) 145–147
question thus arises whether VCE has a role in the diagnosis of patients with suspected coeliac disease. In this issue of Digestive and Liver Disease, Hopper et al. [10] report on a study in which this question was addressed: they studied with upper GI endoscopy + duodenal biopsy and with VCE 21 patients with positive EMA and 23 subjects with negative EMA who served as controls. The rationale of the study is sound, since VCE was studied in the population in which it would be used if the value of this technique was established. Duodenal biopsy showed villous atrophy in 20/21 EMA positive subjects and normal histology in all the EMA negative controls. VCE detected villous atrophy in 17/20 patients with atrophy on duodenal biopsy, and in none of the 23 subjects with normal duodenal histology. Based on these results, the sensitivity, specificity, positive and negative predictive values of VCE in the recognition of villous atrophy were 85, 100, 100 and 88.9%, respectively. Interestingly, Hopper et al. [10] results closely match those of a multicenter study with similar design whose preliminary results we recently presented at the Digestive Disease Week [11]. In that study, 25 patients with suspected CD and positive serology underwent upper GI endoscopy with duodenal biopsy and VCE examination. Overall, capsule endoscopy had a sensitivity of 94.4% and a specificity of 85.7%, with positive and negative predictive values of 94.4 and 85.7%, respectively and positive and negative likelihood ratios of 6.6 and 0.14, respectively. On the other hand, in a study by Biagi et al. [12] the sensitivity of capsule endoscopy ranged between 90.5 and 95.2%, but the specificity was markedly lower (63.6%). Relative weaknesses of Hopper et al. study [10] are the limited number of cases studied and the fact that 95% of patients had severe villous atrophy (Marsh III lesions). In fact, a variable proportion of EMA positive patients may have lesser degrees of villous atrophy, and we do not know how the capsule performs in such patients. Indeed, in Biagi et al. [12] study, which included patients with different degrees of villous atrophy, the correlation between the VCE score and the histologic score was only moderate, casting some doubt on the ability of VCE to reliably recognise mild to moderate degrees of villous atrophy. A further limitation of Hopper et al. study [10] is that the evaluation of capsule findings was done by a single observer, and thus does not clarify the reproducibility and interobserver agreement in the evaluation of capsule findings in CD. In our study [11], a formal evaluation of the interobserver agreement showed a high degree of agreement as evaluated by kappa statistics [13,14]. In addition, in Biagi et al. study [12] the interobserver agreement (kappa statistic) for the recognition of villous atrophy by capsule endoscopy ranged between 0.49 and 0.70, denoting moderate to good agreement. In conclusion, there is mounting evidence that VCE may be useful in the evaluation of patients with coeliac disease. Concerning its use to diagnose CD in patients with suspected disease, a recent consensus meeting on capsule endoscopy concluded that all VCE endoscopists should be able to recognise CD, that the sensitivity and especially the specificity of
the technique need to be assessed in larger trials and that, for the time being, capsule endoscopy offers an alternative to duodenal biopsy in patients unable or unwilling to undergo conventional upper GI endoscopy [15]. Furthermore, VCE may be indicated in patients who have a high suspicion of CD, but in whom the histology is normal or equivocal. Indeed, in a recently published study [16] in patients with positive coeliac serology and negative duodenal histology, VCE detected small bowel lesions compatible with a diagnosis of CD, which was supported by HLA-DQ testing, in 27.5% of cases. Can we foresee a use of VCE as a routine diagnostic tool for the diagnosis and follow-up of CD? Before we answer this question, two main issues need to be addressed: first, the ability of VCE to recognise mild and moderate degrees of villous atrophy must be further assessed, and, second, costutility analyses must be carried out to ascertain whether the cost of the capsule, which is very high compared to that of upper GI endoscopy plus duodenal biopsy, is outweighed by the better acceptability of VCE by patients.
Conflict of interest statement None declared.
References [1] Murray JA, Van Dyke C, Plevak MF, Dierkhising RA, Zinsmeister AR, Melton III LJ. Trends in the identification and clinical features of celiac disease in a North American community, 1950–2001. Clin Gastroenterol Hepatol 2003;1:19–27. [2] Cook B, Oxner R, Chapman B, Whitehead M, Burt M. A 30-year (1970–1999) study of celiac disease in the Canterbury region of New Zealand. N Z Med J 2004;117:U772. [3] Rewers M. Epidemiology of celiac disease: what are the prevalence, incidence and progression of celiac disease? Gastroenterology 2005;128:S47–51. [4] Gheller-Rigoni AI, Yale SH, Abdulkarim AS. Celiac disease: celiac sprue, gluten sensitive enteropathy. Clin Med Res 2004;2:71–2. [5] Marsh MN. Gluten major histocompatibility and the small intestine. A molecular and immunobiological approach to the spectrum of gluten sensitivity. Gastroenterology 1992;102:330–54. [6] Oberhuber G, Granditsch G, Vogelsang H. The histopathology of coeliac disease: time for a standardised report scheme for pathologists. Eur J Gastroenterol Hepatol 1999;11:1185–94. [7] Green PHR. The many faces of celiac disease: clinical presentation of celiac disease in the adult population. Gastroenterology 2005;128:S74–8. [8] Culliford A, Daly J, Diamond B, Rubin Moshe, Green PHR. The value of wireless capsule endoscopy in patients with complicated celiac disease. Gastrointest Endosc 2005;62:55–61. [9] Petroniene R, Dubcenco E, Baker JP, Ottaway CA, Tang SJ, Zanati SA, et al. Given capsule endoscopy in celiac disease: evaluation of diagnostic accuracy and interobserver agreement. Am J Gastroenterol 2005;100:685–94. [10] Hopper AD, Sidhu R, Hurlstone DP, McAlindon ME, Sanders DS. Capsule endoscopy: an alternative to duodenal biopsy for the recognition of villous atrophy in coeliac disease? Digest Liver Dis 2007;39: 140–5.
E. Rondonotti, R. de Franchis / Digestive and Liver Disease 39 (2007) 145–147 [11] de Franchis R, Riccioni ME, Cave D, Pennazio M, Rondonotti E, Schneider D, et al. Video capsule endoscopy for the diagnosis of celiac disease: preliminary results of a multicenter international study. Gastroenterology 2005;128(Suppl. 2):A-82 (abstract). [12] Biagi F, Rondonotti E, Campanella J, Villa F, Bianchi PI, Klersy C, et al. Videocapsule endoscopy and histology for small bowel mucosa evaluation: a comparison performed by blinded observers. Clin Gastroenterol Hepatol 2006;4:998–1003. [13] Landis JR, Koch GG. The measurement of observer agreement for categorical data. Biometrics 1977;33:159–74.
147
[14] Brennan P, Silman A. Statistical methods for assessing observer variability in clinical measures. Br Med J 1992;304:1491–4. [15] Cellier C, Green PH, Collin P, Murray J. ICCE consensus for celiac disease. Endoscopy 2005;37:1055–9. [16] Adler SN, Jacob H, Lijovetzky G, Mulder CJ, Zwiers A. Positive coeliac serology in irritable bowel syndrome patients with normal duodenal biopsies: video capsule endoscopy findings and HLA-DQ typing may affect clinical management. J Gastrointest Liver Dis 2006;15:221–5. doi: 10.1016/j.dld.2006.10.005
145
[31] Badreldin R, Barrett P, Wooff DA, Mansfield J, Yiannakou Y. How good is zoom endoscopy for assessment of villous atrophy in coeliac disease? Endoscopy 2005;37:994–8. [32] Sanders DS, Carter MJ, Hurlstone DP, Pearce A, Ward AM, McAlindon ME, et al. Association of adult coeliac disease with irritable bowel syndrome: a case-control study in patients fulfilling ROME II criteria referred to secondary care. Lancet 2001;358:1504–8. [33] Horoldt BS, McAlindon ME, Stephenson TJ, Hadjivassiliou M, Sanders DS. Making the diagnosis of coeliac disease: is there a role for push enteroscopy? Eur J Gastroenterol Hepatol 2004;16: 1143–6. [34] Wahab PJ, Crusius JB, Meijer JW, Mulder CJ. Gluten challenge in borderline gluten-sensitive enteropathy. Am J Gastroenterol 2001;96:1464–9. [35] Tursi A, Brandimarte G. The symptomatic and histologic response to a gluten-free diet in patients with borderline enteropathy. J Clin Gastroenterol 2003;36:13–7.
Commentary
Diagnosing coeliac disease: Is the videocapsule a suitable tool? E. Rondonotti, R. de Franchis ∗ Department of Medical Sciences, University of Milan and Gastroenterology and GI Endoscopy Unit, Ospedale Maggiore Policlinico, Mangiagalli and Regina Elena Foundation, Milan, Italy Available online 14 December 2006
In Western countries, coeliac disease (CD) has an estimated incidence of 2–13 cases/100,000 people per year [1,2] and a prevalence of 0.7–2% [3]. CD is characterised by intolerance to gluten: in genetically predisposed subjects, ingestion of gluten results in small intestinal mucosal inflammation and damage [4]. Such damage ranges from mild – with an increase in the number of intraepithelial lymphocytes and crypt hyperplasia – to severe, with various degrees of villous atrophy [5,6]. The most typical clinical manifestations of CD are abdominal symptoms, diarrhoea, growth failure and malabsorption of various nutrients. Atypical manifestations such as endocrine dysfunction, anaemia, liver function abnormalities, osteoporosis, infertility, cerebellar ataxia, dermatitis herpetiformis, and alopecia may also occur. However, the symptoms are often vague or subclinical, whereas about 10% of diagnosed patients are totally asymptomatic [3,7]. It is estimated that, for every case of CD identified, 3–7 remain undiagnosed [3]. Classically, the finding of small bowel villous atrophy on duodenal biopsy is the mainstay of diagnosis. Nowadays, serological testing for anti-endomysial (EMA) and antitissue transglutaminase (anti-tTG) antibodies has become the initial diagnostic test in subjects with suspected CD, ∗ Corresponding author. Tel.: +39 02 5503 5331/2; fax: +39 02 5032 0747.
E-mail address: [email protected] (R. de Franchis)
since these antibodies have combined positive and negative predictive values in excess of 90%. Therefore, the current diagnostic algorithm for patients with suspected coeliac disease includes serological testing for EMA and/or anti-tTG followed by upper GI endoscopy with multiple duodenal biopsies. However, duodenal biopsy is not ideal as the gold standard for the diagnosis of CD: obtaining adequate and properly oriented tissue samples may be difficult, mucosal lesions may be patchy and thus missed by the biopsy, and, in some cases, the most severe mucosal changes occur in the jejunum, which is not accessible to conventional upper GI endoscopy [3]. In addition, endoscopy is perceived as unpleasant by some patients, and this limits its use, especially by asymptomatic subjects. As a result, a proportion of potential candidates for duodenal biopsy choose to defer the procedure. Over the last 6 years, videocapsule endoscopy (VCE) has become an important diagnostic tool for the evaluation of the small intestine, since it has been shown to be superior to other diagnostic tools for the diagnosis of a variety of small bowel diseases, including refractory CD [8]. VCE produces high quality images of the small bowel mucosa, with an eight-fold magnification and is able to detect minute mucosal details, including changes in intestinal villi. For these reasons VCE may be a useful tool for the diagnosis of CD; indeed, in a pilot study on VCE in 10 patients with untreated CD, the characteristic villous atrophy was apparent in all patients [9]. The
146
E. Rondonotti, R. de Franchis / Digestive and Liver Disease 39 (2007) 145–147
question thus arises whether VCE has a role in the diagnosis of patients with suspected coeliac disease. In this issue of Digestive and Liver Disease, Hopper et al. [10] report on a study in which this question was addressed: they studied with upper GI endoscopy + duodenal biopsy and with VCE 21 patients with positive EMA and 23 subjects with negative EMA who served as controls. The rationale of the study is sound, since VCE was studied in the population in which it would be used if the value of this technique was established. Duodenal biopsy showed villous atrophy in 20/21 EMA positive subjects and normal histology in all the EMA negative controls. VCE detected villous atrophy in 17/20 patients with atrophy on duodenal biopsy, and in none of the 23 subjects with normal duodenal histology. Based on these results, the sensitivity, specificity, positive and negative predictive values of VCE in the recognition of villous atrophy were 85, 100, 100 and 88.9%, respectively. Interestingly, Hopper et al. [10] results closely match those of a multicenter study with similar design whose preliminary results we recently presented at the Digestive Disease Week [11]. In that study, 25 patients with suspected CD and positive serology underwent upper GI endoscopy with duodenal biopsy and VCE examination. Overall, capsule endoscopy had a sensitivity of 94.4% and a specificity of 85.7%, with positive and negative predictive values of 94.4 and 85.7%, respectively and positive and negative likelihood ratios of 6.6 and 0.14, respectively. On the other hand, in a study by Biagi et al. [12] the sensitivity of capsule endoscopy ranged between 90.5 and 95.2%, but the specificity was markedly lower (63.6%). Relative weaknesses of Hopper et al. study [10] are the limited number of cases studied and the fact that 95% of patients had severe villous atrophy (Marsh III lesions). In fact, a variable proportion of EMA positive patients may have lesser degrees of villous atrophy, and we do not know how the capsule performs in such patients. Indeed, in Biagi et al. [12] study, which included patients with different degrees of villous atrophy, the correlation between the VCE score and the histologic score was only moderate, casting some doubt on the ability of VCE to reliably recognise mild to moderate degrees of villous atrophy. A further limitation of Hopper et al. study [10] is that the evaluation of capsule findings was done by a single observer, and thus does not clarify the reproducibility and interobserver agreement in the evaluation of capsule findings in CD. In our study [11], a formal evaluation of the interobserver agreement showed a high degree of agreement as evaluated by kappa statistics [13,14]. In addition, in Biagi et al. study [12] the interobserver agreement (kappa statistic) for the recognition of villous atrophy by capsule endoscopy ranged between 0.49 and 0.70, denoting moderate to good agreement. In conclusion, there is mounting evidence that VCE may be useful in the evaluation of patients with coeliac disease. Concerning its use to diagnose CD in patients with suspected disease, a recent consensus meeting on capsule endoscopy concluded that all VCE endoscopists should be able to recognise CD, that the sensitivity and especially the specificity of
the technique need to be assessed in larger trials and that, for the time being, capsule endoscopy offers an alternative to duodenal biopsy in patients unable or unwilling to undergo conventional upper GI endoscopy [15]. Furthermore, VCE may be indicated in patients who have a high suspicion of CD, but in whom the histology is normal or equivocal. Indeed, in a recently published study [16] in patients with positive coeliac serology and negative duodenal histology, VCE detected small bowel lesions compatible with a diagnosis of CD, which was supported by HLA-DQ testing, in 27.5% of cases. Can we foresee a use of VCE as a routine diagnostic tool for the diagnosis and follow-up of CD? Before we answer this question, two main issues need to be addressed: first, the ability of VCE to recognise mild and moderate degrees of villous atrophy must be further assessed, and, second, costutility analyses must be carried out to ascertain whether the cost of the capsule, which is very high compared to that of upper GI endoscopy plus duodenal biopsy, is outweighed by the better acceptability of VCE by patients.
Conflict of interest statement None declared.
References [1] Murray JA, Van Dyke C, Plevak MF, Dierkhising RA, Zinsmeister AR, Melton III LJ. Trends in the identification and clinical features of celiac disease in a North American community, 1950–2001. Clin Gastroenterol Hepatol 2003;1:19–27. [2] Cook B, Oxner R, Chapman B, Whitehead M, Burt M. A 30-year (1970–1999) study of celiac disease in the Canterbury region of New Zealand. N Z Med J 2004;117:U772. [3] Rewers M. Epidemiology of celiac disease: what are the prevalence, incidence and progression of celiac disease? Gastroenterology 2005;128:S47–51. [4] Gheller-Rigoni AI, Yale SH, Abdulkarim AS. Celiac disease: celiac sprue, gluten sensitive enteropathy. Clin Med Res 2004;2:71–2. [5] Marsh MN. Gluten major histocompatibility and the small intestine. A molecular and immunobiological approach to the spectrum of gluten sensitivity. Gastroenterology 1992;102:330–54. [6] Oberhuber G, Granditsch G, Vogelsang H. The histopathology of coeliac disease: time for a standardised report scheme for pathologists. Eur J Gastroenterol Hepatol 1999;11:1185–94. [7] Green PHR. The many faces of celiac disease: clinical presentation of celiac disease in the adult population. Gastroenterology 2005;128:S74–8. [8] Culliford A, Daly J, Diamond B, Rubin Moshe, Green PHR. The value of wireless capsule endoscopy in patients with complicated celiac disease. Gastrointest Endosc 2005;62:55–61. [9] Petroniene R, Dubcenco E, Baker JP, Ottaway CA, Tang SJ, Zanati SA, et al. Given capsule endoscopy in celiac disease: evaluation of diagnostic accuracy and interobserver agreement. Am J Gastroenterol 2005;100:685–94. [10] Hopper AD, Sidhu R, Hurlstone DP, McAlindon ME, Sanders DS. Capsule endoscopy: an alternative to duodenal biopsy for the recognition of villous atrophy in coeliac disease? Digest Liver Dis 2007;39: 140–5.
E. Rondonotti, R. de Franchis / Digestive and Liver Disease 39 (2007) 145–147 [11] de Franchis R, Riccioni ME, Cave D, Pennazio M, Rondonotti E, Schneider D, et al. Video capsule endoscopy for the diagnosis of celiac disease: preliminary results of a multicenter international study. Gastroenterology 2005;128(Suppl. 2):A-82 (abstract). [12] Biagi F, Rondonotti E, Campanella J, Villa F, Bianchi PI, Klersy C, et al. Videocapsule endoscopy and histology for small bowel mucosa evaluation: a comparison performed by blinded observers. Clin Gastroenterol Hepatol 2006;4:998–1003. [13] Landis JR, Koch GG. The measurement of observer agreement for categorical data. Biometrics 1977;33:159–74.
147
[14] Brennan P, Silman A. Statistical methods for assessing observer variability in clinical measures. Br Med J 1992;304:1491–4. [15] Cellier C, Green PH, Collin P, Murray J. ICCE consensus for celiac disease. Endoscopy 2005;37:1055–9. [16] Adler SN, Jacob H, Lijovetzky G, Mulder CJ, Zwiers A. Positive coeliac serology in irritable bowel syndrome patients with normal duodenal biopsies: video capsule endoscopy findings and HLA-DQ typing may affect clinical management. J Gastrointest Liver Dis 2006;15:221–5. doi: 10.1016/j.dld.2006.10.005