Rapid Responses to:

RESEARCH: Andrew D Hopper, Simon S Cross, David P Hurlstone, Mark E McAlindon, Alan J Lobo, Marios Hadjivassiliou, Marion E Sloan, Simon Dixon, and David S Sanders Pre-endoscopy serological testing for coeliac disease: evaluation of a clinical decision tool BMJ 2007; 334: 729 [Abstract] [Full text]

Rapid Responses: Submit a response to this article

Rapid Responses published:

Please, imagine a modern role for the modern endoscopy in diagnosing coeliac disease

Giovanni Cammarota, Paola Cesaro   (6 April 2007)

a role for jejunal biopsy and also for capsule endoscopy

oscar,m jolobe   (11 April 2007)

Duodenal biopsy the gold standard?

Richard Nahas   (11 April 2007)

A coeliac decision tool needs to be developed for children

Jonas F. Ludvigsson, Anneli Ivarsson   (14 April 2007)

Concerns regarding the choice of serological testing

Dr Mohammed Y Karim, Dr Helen Griffiths, Dr Sarah Deacock   (28 April 2007)

Serological testing in children with Coeliac Disease

Hassan K Chaudhry   (30 April 2007)

'Suck it 'n' see' approach to testing for coeliacs disease

Cheryl Hill   (15 May 2007)

Dermatitis herpetiformis as a diagnostic tool for coeliac disease

Daniele Torchia, Marzia Caproni, and Paolo Fabbri   (6 June 2007)

Improving the diagnosis of Coeliac Disease: the key role of endoscopists

Emilio Brocchi, Raffaele Pezzilli, Roberto Corinaldesi   (7 June 2007)

Please, imagine a modern role for the modern endoscopy in diagnosing coeliac disease 6 April 2007
Giovanni Cammarota, Assistant Professor Endoscopy Unit, Department of Internal Medicine, A Gemelli University Hospital, 00168, Rome, Italy, Paola Cesaro Send response to journal: Re: Please, imagine a modern role for the modern endoscopy in diagnosing coeliac disease	We read with attention the paper by Hopper et al (7 April BMJ issue) (1). We have to do some considerations. The authors validated a diagnostic method of detecting all cases of celiac disease in subjects referred for EGD. People with positive celiac disease- related serology and high risk symptoms (such as diarrhoea, weight loss, anaemia) had a sensitivity for celiac disease of 100%. They also found that a proportion of patients with positive serology turn off not to have celiac disease on biopsy. This should prompt reconsideration of the need for a life-long gluten-free diet. On my opinion, in this as in many other studies on celiac disease, the role of the modern endoscopy in evaluating where and when biopsy to perform duodenal biopsy is underestimated. For example, high risk patients with positive serology and not found to be coeliacs on biopsy could have a villous damage limited to the proximal part of the duodenum and, therefore, the biopsy sampling could have been untargeted. The new generation of video-endoscopy combined with a simple method called “immersion technique” (consisting in injecting a few millilitres of water into the duodenum after removing air from the lumen) can help to visualise in vivo the duodenal villi during a routinely EGD. This approach may allow to target biopsy on area of duodenal mucosa where villi are absent and help to detect patchying forms of celiac disease (2, 3). On the other hand, the above mentioned “immersion technique” may be at the basis of new and cost-saving endoscopy-based approach to the diagnosis of coeliac disease. For example, high risk patients can be easily detected to have a total absence of villi (flat mucosa) and, therefore, in these cases, the biopsy sampling and histological analysis could be avoided without interfere with the clinical assessment. This approach may result cost-saving in diagnosing subjects with Marsh’s type-3 coeliac disease (4, 5). Biopsy could be reserved for high risk patients in whom villi are visible at endoscopy, in order to detect celiac patients with type-1 and - 2 villous atrophy (according to the Marsh’s classification). We are aware that further studies including cost analysis and outcome are needed to verify the reproducibility of the diagnostic strategy we propose, but in prospective the modern endoscopy should be thought as able to play a more incisive role in this context than merely that to obtain biopsy specimens for histological analysis. References 1) Hopper AD, Cross SS, Hurlstone DP, McAlindon ME, Lobo AJ, Hadjivassiliou M, et al. Pre-endoscopy serological testing for celiac disease: evaluation of a clinical decision tool. BMJ 2007;729 (7 April). 2) Bonamico M, Mariani P, Thanasi E, Ferri M, Nenna R, Tiberti C, et al. Patchy villous atrophy of the duodenum in childhood celiac disease. J Pediatr Gastroenterol Nutr 2004; 38: 204–7. 3) Cammarota G, Cesaro P, La Mura R, Martino A, Cazzato, A. Miele L, et al. Role of the “immersion technique” in diagnosing celiac disease with villous atrophy limited to the duodenal bulb. J Clin Gastroenterol 2007 (in press) 4) Cammarota G, Gasbarrini A, Gasbarrini G. No more biopsy in the diagnostic work-up of celiac disease. Gastrointest Endosc 2005; 62: 119–121. 5) Cammarota G, Cesaro P, Martino A, Zuccalà G, Cianci R, Nista E, et al. High accuracy and cost-effectiveness of a biopsy-avoiding endoscopic approach in diagnosing coeliac disease. Aliment Pharmacol Ther 2006; 23: 61-69. Competing interests: None declared
a role for jejunal biopsy and also for capsule endoscopy 11 April 2007
oscar,m jolobe, retired geriatrician 1 the Lodge, 842 Wilmslow road, didsbury, Manchester, M20 2RN Send response to journal: Re: a role for jejunal biopsy and also for capsule endoscopy	The assertion that the "gold standard" diagnostic test for coeliac disease is the demonstration of villous atrophy on duodenal biopsy(1) should be qualified to encompass the role of jejunal biopsy via push enteroscopy, given the fact that the disease may occasionally involve the jejunum to the exclusion of the duodenum(2). Furthermore, during enteroscopy, repeat duodenal biopsy performed in addition to jejunal biopsy may sometimes reveal evidence of coeliac disease missed during previous gastroscopy(2). The latter phenomenon is attributable to the patchy involvement of the duodenum by coeliac diseasae(3). Given the fact that the diagnostic accuracy of histological diagnosis of coeliac disease depends not only on the degree and quality of communication between the clinician and an experienced histopathologist(4), but also on the quality of biopsy samples, the latter being currently acknowledged to be suboptimal(5), a case can be made for the proposition that "the difficulty in the interpretation of intestinal biopsy makes the role of histology as the stand-alone diagnostic tool questionable"(5). Accordingly, given the impressively high positive and negative predictive values cited by the authors for the combined measurement of IgA antibodies to tissue transglutaminase and IgA endomyseal antibodies(1), a case might be made for an alternative "gold standard" consisting of the combination of positive serology and positive imaging by capsule endoscopy. As with histological evaluation of suspected coeliac disease, evaluation by capsule endoscopy depends, not only on the quality of images but also on the experience of the capsule endoscopist, perfect interobserver agreement(kappa=1.0) being obtained between experienced experienced investigators, with the result that overall sensitivity of this modality for detecting villous atriphy can be as high 70%, specificity 100%, positive predictive value 100%, negative predictive value 77%(6). References (1) Hopper AD., Cross SS., Hurlstone DP et al Pre-endoscopy serological testing for coeliac disease: evaluation of a clinical decision tool BMJ 2007:334:729-32 (2)Horoldt B., McAlindon ME., Stephenson TJ et al Making the diagnosis of coeliac disease: is there a role for push enteroscopy? European Journal of Gastroenetrology and Hepatology 2004:16:1143-6 ( 3)Scott BB and Losowsky MS Patchiness and duodenal-jejunal variation of the mucosal abnormality in coeliac disease and dermatitis herpetiformis Gut 1976:17:984-92 (4)Serra S and Jani PA An approach to duodenal biopsies Journal of Clinical Pathology 2006:59:1133-50 (5)Collin P., Kaukinen K., Vogelsang H et al Antiendomysial and antihuman recombinant tissue transglutaminase antibodies in the diagnosis of coeliac disease: a biopsy-proven European multicentre study European Journal of Gastroeneterology and Hepatology 2005:17:85-91 (6)Petronieme R., Dubcenco E., Baker JP et al Given capsule endoscopy in celiac disease: evaluation of diagnostic acucuracy and interobsrver agreement American Journal of Gastroeneterology 2005:100:685-94 Competing interests: None declared
Duodenal biopsy the gold standard? 11 April 2007
Richard Nahas, MD 6 Deakin St Ottawa Canada K2E1B3 Send response to journal: Re: Duodenal biopsy the gold standard?	This study has reassuringly demonstrated that all patients with an abnormal duodenal biopsy will have either a positive tissue transglutaminase test or high-risk clinical presentation, or both. The assumption made by the study is that all patients whose symptoms are linked to gluten will have an abnormal duodenal biopsy. There is a sense among my clinician colleagues that this is not the case. To my knowledge, there is no good-quality evidence comparing duodenal biopsy to a gluten-free trial and re-challenge. This latter therapeutic trial, while subject to patient bias, has yielded dramatic results in some biopsy -negative patients Competing interests: None declared
A coeliac decision tool needs to be developed for children 14 April 2007
Jonas F. Ludvigsson, MD. PhD. Dept. of Paediatrics, Örebro University Hospital and Karolinska Institutet, Stockholm, Sweden, Anneli Ivarsson Send response to journal: Re: A coeliac decision tool needs to be developed for children	It is with great interest that we read the paper by Hopper et al about a coeliac disease clinical decision tool (7 April BMJ issue) (1). This paper takes on the important challenge of increasing the detection rate of coeliac disease in a cost-effective manner. The authors show that a positive tissue transglutaminase autoantibody result has a high sensitivity for coeliac disease, although still a comparatively low positive predictive value (for a detailed discussion, please see the review by Rostom et al (2)). Antibody-negative cases of coeliac disease were all individuals with diarrhoea, weight loss or anaemia. Hopper et al combine the use of tissue transglutaminase autoantibody positivity and the presence of certain clinical features into a clinical decision tool selecting individuals for duodenal biopsy (1), and in doing so increase the detection rate of coeliac disease. The study by Hopper et al has an important limitation not mentioned by the authors (1), it is restricted to adults. However, coeliac disease often presents in childhood when symptoms and signs are often different from those in adulthood (3, 4). It may therefore be inappropriate to use the clinical characteristics suggested by Hopper et al (1) when dividing children into high- and low-risk groups with respect to coeliac disease. The second part of the clinical decision tool of Hopper et al is testing with tissue transglutaminase autoantibodies (1). Also here clinicians need to consider the implications of age. In a recent review by Rostom et al (5), the pooled sensitivity of human tissue transglutaminase IgA autoantibodies was lower in children (95.7%) than in adults (98.1%), thus more false negative cases can be expected. We therefore suggest that the clinical decision tool proposed by Hopper et al (1) should be child adapted, and thereafter tested prospectively in an unselected paediatric population. In adults, however, it seems that we now have a much useful clinical decision tool to increase detection of coeliac disease. Jonas F Ludvigsson MD PhD; Anneli Ivarsson MD PhD REFERENCES 1 Hopper AD, Cross SS, Hurlstone DP, McAlindon ME, Lobo AJ, Hadjivassiliou M, et al. Pre-endoscopy serological testing for coeliac disease: evaluation of a clinical decision tool. Bmj 2007;334(7596):729. 2 Rostom A, Murray JA, Kagnoff MF. American Gastroenterological Association (AGA) Institute technical review on the diagnosis and management of celiac disease. Gastroenterology 2006;131(6):1981-2002. 3 Fasano A. Clinical presentation of celiac disease in the pediatric population. Gastroenterology 2005;128(4 Suppl 1):S68-73. 4 Ludvigsson JF, Ansved P, Falth-Magnusson K, Hammersjo JA, Johansson C, Edvardsson S, et al. Symptoms and Signs Have Changed in Swedish Children With Coeliac Disease. J Pediatr Gastroenterol Nutr 2004;38(2):181-186. 5 Rostom A, Dube C, Cranney A, Saloojee N, Sy R, Garritty C, et al. The diagnostic accuracy of serologic tests for celiac disease: a systematic review. Gastroenterology 2005;128(4 Suppl 1):S38-46. Competing interests: None declared
Concerns regarding the choice of serological testing 28 April 2007
Dr Mohammed Y Karim, Consultant Immunologist Frimley Park Hospital, Dr Helen Griffiths, Dr Sarah Deacock Send response to journal: Re: Concerns regarding the choice of serological testing	Dear Sir, We read with interest the recent article on pre-endoscopy serological testing for coeliac disease from Dr Hopper et al (BMJ 2007; 334: 729). While the paper does suggest a useful algorithm for investigation of coeliac disease, our attention was drawn to the particularly low positive predictive value (PPV), 28.6%, of the tissue transglutaminase (TTG) antibody test. Even within the high-risk group of patients, only 64 out of 154 TTG positive patients were shown to have coeliac disease. This implies that 90 out of 154 TTG antibody-positive patients did not have coeliac disease. The false positive rate in the low risk group was even higher as only 6 out of 91 TTG positive patients were found to have coeliac disease. Other authors have quoted PPV’s of around 80% (1), however it is well known that a small proportion of false positive TTG antibodies can be found, such as in patients with high IgA levels e.g. chronic liver disease or IgA paraproteins. The false positive rate for this particular ELISA assay is unacceptably high. False negative histology due to inappropriate biopsy sampling is unlikely to explain all of these positives. Although automation of TTG using enzyme-linked immunosorbent assay (ELISA) allows higher throughput of samples, it should not be at the loss of a good PPV. It would therefore be most instructive to know if the authors have data in this group of patients with respect to endomysial antibodies (EMA). The authors do comment on the debate regarding the exact antibody test to perform in patients referred for endoscopy, and indeed our centre does adopt the two-step approach that they mention, namely screening with TTG followed by EMA in patients with positive TTG results. They go on to comment that using TTG antibodies alone was adequate and cheap and that no cases of coeliac disease were missed. However although the negative predictive value of this test has been demonstrated, what has been clearly shown is that the value of a positive TTG antibody is not particularly useful in this study. In summary, what we would say is sometimes “old is gold”, and we certainly think it would be worthwhile re-visiting the data with respect to EMA to see if more specific serological results are obtained. Furthermore, from a cost implication, over 90% of the patients with TTG antibodies in the low risk group did not have coeliac disease, implying that a large number of patients will have undergone endoscopy and biopsy unnecessarily and at great expense, which might have been obviated if EMA testing had been performed, or perhaps a combination of TTG & EMA. 1.Hill PG, Forsyth JM, Semeraro D, Holmes GK. IgA antibodies to human tissue transglutaminase: audit of routine practice confirms high diagnostic accuracy. Scand J Gastroenterol 2004; 39: 1078-82 Dr Yousuf Karim MRCP MRCPath, Dr Helen Griffiths MD FRCPath, Dr Sarah Deacock PhD FRCP FRCPath Competing interests: None declared
Serological testing in children with Coeliac Disease 30 April 2007
Hassan K Chaudhry, Clinical Attachee WN1 2NN Send response to journal: Re: Serological testing in children with Coeliac Disease	Initial screening of suspected cases of CD is usually carried out using serological tests. Those available are: • Anti gliadin antibodies (AGA) • Anti endomysial antibodies (EMA) • Anti tissue transglutaminase (tTG) However, serologic testing for Coeliac Disease in children less than 5 years of age may be less reliable and requires further study. Approximately 2% of symptomatic children with Coeliac disease are IgA deficient. Therefore, if testing for Coeliac Disease in children with suspicious symptoms, measurement of quantitative serum IgA can help when the tTG IgA is low. Symptoms depend on the age of onset of the disease and the extent of intestinal involvement. In infancy it appears after weaning on to gluten containing foods. The genetic disorders determine the age of onset as well as the extent of intestinal involvement. Although the classic picture of an unhappy blond child with slender limbs, wasted buttocks and prominent abdomen is well known, gastrointestinal symptoms predominate in children diagnosed within the first two years of life. Therefore, young children primarily display diarrhea, vomiting, abdominal pain and abdominal distention. Failure to thrive, anorexia, and irritability often are present. Some children may display severe symptoms with profuse diarrhea, leading to severe dehydration (Coeliac crisis). Various diseases, autoimmune endocrinopathies, connective tissue and collagen disorders have been reported in association with celiac disease. A high proportion of patients with autoimmune diseases such as Sjogren’s syndrome, Hashimoto’s thyroiditis, autoimmune thrombopenia and insulin dependent diabetes mellitus, have abnormal intestinal mucosa consistent with celiac disease. It is clearly established that a high proportion of patients (60%) with dermatitis herpetiformis have celiac disease. The prevalence of HLA- DR3, HLA –DQw2, and circulating antigliadin antibodies in this group parallels that in coeliac disease. There is also a relationship between coeliac disease and Down syndrome. The reported prevalence of celiac disease among patients with Down syndrome varies from 4-4.5%.Patients with cystic fibrosis have a 5-fold risk of Coeliac disease compared with the general population(5:1000). A sweat test to exclude cystic fibrosis is mandatory in all children with celiac disease at the time of diagnosis, while every child with cystic fibrosis who displays protracted symptoms of malabsorption, despite pancreatic enzyme supplementation, should undergo jejunal biopsy. The definitive diagnosis is confirmed when symptoms completely resolve following treatment with a gluten free diet (GFD) in a previously symptomatic individual with characteristic histological changes on SI biopsy. Following treatment with a GFD a previously positive serological test becoming negative further supports the diagnosis. A second biopsy to demonstrate normalized histology following a GFD is no longer recommended. However, a gluten challenge should be carried out in children (a) in whom the initial biopsy was performed before 2 years of age (because of the risk of confusion with many other conditions such as cow's milk sensitive enteropathy, postenteritis enteropathy and giardiasis) References: 1)Hopper AD, Cross SS, Hurlstone DP, McAlindon ME, Lobo AJ, Hadjivassiliou M, et al. Pre-endoscopy serological testing for coeliac disease: evaluation of a clinical decision tool. Bmj 2007;334(7596):729. 2) Parveen Kumar, Michael Clark et al. Kumar & Clark Clinical Medicine.5:291-293. 3) Eleni Mihailidi, Penelope Paspalaki et al. “Celiac Disease: A Pediatric Perspective”, International Pediatrics 2003:18: 142-148. 4) DAVID A. NELSEN. “Gluten-Sensitive Enteropathy (Celiac Disease): More Common Than You Think” 2002:66(12):2269. Competing interests: None declared
'Suck it 'n' see' approach to testing for coeliacs disease 15 May 2007
Cheryl Hill, wholefood sales High Wycombe Send response to journal: Re: 'Suck it 'n' see' approach to testing for coeliacs disease	As a lay-person whose family is one of a growing number experiencing many benefits from a wheat and dairy free diet, I just wondered; is it ever sugguested to patients that a wheat or gluten free diet may indeed alleviate a very wide range of symptoms regardless of whether it is celiacs or not? Especially these types of symptoms? I am suggesting that a suck it and see 'approach' might not only be cheaper, but infinitely preferable for both parties than going in for a procedure; if the chances of success are high either way, does it matter what the cause is? I write with confidence about 'alternative' treatments for candida or for 'leaky gut' which use diet to cure or improve many conditions. Competing interests: None declared
Dermatitis herpetiformis as a diagnostic tool for coeliac disease 6 June 2007
Daniele Torchia, Researcher University of Florence, 50121 Italy, Marzia Caproni, and Paolo Fabbri Send response to journal: Re: Dermatitis herpetiformis as a diagnostic tool for coeliac disease	Recently on the BMJ, a research article by Hopper et al. (1) showed that a positive serological test for IgA to tissue transglutaminase (tTG) has a 90.9% sensitivity in the diagnosis of coeliac disease (CD). Sensitivity raised to a 100% by means of duodenal biopsy. Related comments appreciated the study and recommended its evaluation in primary care settings. (2,3) We point out that another possibility to detect CD without performing a duodenal biopsy exists, i.e. to diagnose dermatitis herpetiformis (DH). DH is a pruritic polymorphous skin disease that is now considered as the cutaneous manifestation of CD. (4) The diagnostic gold standard for DH is direct immunofluorescence assay on perilesional skin, that shows granular IgA deposits at the dermoepidermal junction in the great majority of patients. Clinical examination, skin histopathology and dosage of antibodies to tTG achieve a definite diagnosis in the remaining cases. (5) Since the lifelong gluten-free diet is an effective treatment of both DH and CD, we believe that a duodenal biopsy may not be routinely performed in such patients. References (1) Hopper AD, Cross SS, Hurlstone DP, McAlindon ME, Sanders S, Lobo AJ, et al. Pre-endoscopy serological testing for coeliac disease: evaluation of a clinical decision tool. BMJ 2007;334:729. (2) Jones R. Coeliac disease in primary care. BMJ 2007;334:704-5. (3) Graber ML, Kumar A. Commentary: Reaching a milestone in diagnosing coeliac disease. BMJ 2007;334:732. (4) Oxentenko AS, Murray JA. Celiac disease and dermatitis herpetiformis: the spectrum of gluten-sensitive enteropathy. Int J Dermatol 2003;42:585-7. (5) Caproni M, Cardinali C, Renzi D, Calabro A, Fabbri P. Tissue transglutaminase antibody assessment in dermatitis herpetiformis. Br J Dermatol 2001;144:196-7. Competing interests: None declared
Improving the diagnosis of Coeliac Disease: the key role of endoscopists 7 June 2007
Emilio Brocchi, University Researcher Departement of Internal Medicine and Gastroenterology, University of Bologna, Italy, Raffaele Pezzilli, Roberto Corinaldesi Send response to journal: Re: Improving the diagnosis of Coeliac Disease: the key role of endoscopists	Dear Sir, we read with great interest and favour the paper by Hopper et al. (1)and wish to make some considerations about it. Patients referred for an upper GI endoscopy may be considered as a "risk" group for Coeliac Disease (CD): in published data, prevalence of CD in patients submitted to upper GI endoscopy ranges from 1% to 5,2% (1), this depending on the fact that possible not specific gastrointestinal symptoms due to CD may induce the unaware general practitioner to suggest a gastroscopy (2). Endoscopists involved at this point have a crucial role in the diagnosis: they deal with a notable number of celiac patients, but often unsuspected; how could they be alerted about performing duodenal biopsies, considered as the gold standard for diagnosis? An exhaustive answer is given by the study of Hopper et al. (1), in which a pre-endoscopy serological test for CD is proposed, toghether with a clinical decision tool based on the presence of "high" or "low" risk symtoms for CD. The utilized serological test was a standard commercially available Elisa assay to measure IgA antibodies to tissue transglutaminase in the serum, requiring some technical times and delay to give results; an interesting alternative option that could be adopted, as authors suggested in the subset "Discussion", is performing the test in a rapid fashion,utilizing a drop of whole blood (3). Thus, two key points of the study must be stressed in our opinion: 1) to perform the serological test in all patients submitted to endoscopy; 2) to perform the serological test in a rapid fashion, possibly just in the endoscopy room. In this way, duodenal biopsies could be quickly taken in those patients with positive serological results. Moreover, biopsies should be taken from those patients with negative results but with "high risk" symtoms or (we must remember!) with endoscopic signs (4): in this last respect, besides to note possible typical markers (loss of folds, nodules, scalloped folds and mosaic appearance), we are in favour of the use of the "immersion" technique (5)(very simple and taking few seconds) that, applied routinely in the subset of patients with negative serological results, could give additional informations on possible villous alterations. This simple algorithm, although with an additional but reasonable cost of about 6 Euro for each patient (3), should increase the detection rate of CD in patients submitted to an upper GI endoscopy. In conclusion, endoscopists should be aware of this new possibility and begin widespread hunting for celiac patients. REFERENCES 1)Hopper AD, Cross SS, Hurlstone DP, McAlindon ME, Lobo AJ, Hadjivassiliou M et al. Pre- endoscopy serological testing for celiac disease: evaluation of a clinica decision tool. BMJ 2007 Mar 23; [Epub ahead of print]doi: 10.1136/bmj.39133.668681.BE 2)Brocchi E, Bonora M, Epifanio G, Corinaldesi R. Hunting for celiac patients. Digest Liver Dis 2003; 35: 749-750. 3)Nemec G, Ventura A, Stefano M, Leo GD, Baldas V, Tommasini A et al. Looking for celiac disease: diagnostic accuracy of two rapid commercial assays. Am J Gastroenterol 2006; 101: 1597-600. 4)Brocchi E, Mangia L, Misitano B, Epifanio G, Corinaldesi R, Bonvicini F et al. Endoscopic markers in adult celiac disease. Digest Liver Dis 2002; 34: 177-182. 5)Cammarota G, Pirozzi GA, Martino A, Zuccala G, Cianci R, Cuoco L et al. Reliability of the immersion technique during routine upper endoscopy for detection of abnormalities of duodenal villi in patients with dyspepsia. Gastrointest Endosc 2004; 60 (2): 223-8. Competing interests: None declared