Annals of Medicine, 2014; 46: 430–433 © 2014 Informa UK, Ltd. ISSN 0785-3890 print/ISSN 1365-2060 online DOI: 10.3109/07853890.2014.913378
ORIGINAL ARTICLE
A second duodenal biopsy is necessary in the follow-up of adult coeliac patients Federico Biagi, Claudia Vattiato, Simona Agazzi, Davide Balduzzi, Annalisa Schiepatti, Paolo Gobbi & Gino Roberto Corazza
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Coeliac Centre/First Department of Internal Medicine, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Italy
Introduction. Coeliac disease is a chronic enteropathy requiring a close follow-up. However, the best way to follow up coeliac patients has not yet been established. In the last 14 years, we have been offering patients a thorough series of periodical examinations including a histological re-evaluation at 12–18 months. Patients and methods. The notes of all coeliac patients attending our clinic between September 1999 and March 2013 were examined. Results. Data from 317 adult patients were collected. Duodenal biopsy showed a lack of satisfactory histological response in 25/317 patients; endomysial antibodies were still positive in 76, and diet adherence and clinical response were unsatisfactory in 58 and 97, respectively. Correlations of serological data, clinical response, and diet adherence with histological findings were evaluated. Although the P values showed statistically significant differences, sensitivity and specificity were disappointing: 64% and 80% for serological response, 48% and 71% for clinical response, 56% and 85% for diet adherence. Conclusions. After 12–18 months on a gluten-free diet, 8% of the patients do not present a satisfactory histological response; only some of them could have been identified with a serological and/ or clinical re-evaluation. Therefore, a duodenal biopsy seems to be the only tool that could identify patients with unsatisfactory histological response. Key words: Celiac disease, complications, endomysial antibodies, follow-up, gluten-free diet
Key messages • The need for a regular follow-up of coeliac patients is unquestionable. However, a consensus on timing and methods to follow up coeliac patients is at present still lacking. • Histological response was unsatisfactory in 8% of the coeliac patients on a gluten-free diet. • Clinical and serological response could not have been used to predict unsatisfactory histological response. A duodenal biopsy is necessary in the follow-up of adult coeliac patients.
unquestionable. This was already recognized in the early 1990s and confirmed repeatedly in the following years (2–4). In spite of this, a consensus on timing and methods to follow up coeliac patients is at present still lacking. Not only do different centres follow up coeliac patients with different methods and different timing, but it has also not been clarified whether CD patients should be followed up by general practitioners, gastroenterologists, or dieticians (4,5). In the last 14 years, we have been offering coeliac patients attending our unit a thorough series of periodical clinical and serological examinations which include a histological re-evaluation at 12–18 months. The aim of the present study is, therefore, to analyse the data we retrospectively collected in order to establish the best method to follow up coeliac patients.
Introduction Coeliac disease (CD) is a gluten-dependent enteropathy characterized by the need for a gluten-free diet (GFD). Providing that a strict and life-long GFD is maintained, the prognosis is excellent in the vast majority of patients. To start and maintain a strict GFD is, however, difficult, and patients need to be educated and regularly followed up. Another reason for checking coeliac patients periodically is the increased mortality of this condition, mainly due to its complications that can occur even after several years (1). The need for a regular follow-up is therefore
Patients and methods Data collection The clinical notes of all the patients affected by CD on a GFD attending our clinic between September 1999 and March 2013 were examined. All the patients had been diagnosed on the basis of an upper gastrointestinal endoscopy with duodenal biopsies showing frank villous atrophy and positive endomysial or tissue transglutaminase antibodies. These investigations were performed
Correspondence: Dr Federico Biagi, Coeliac Centre/1st Department of Internal Medicine, Fondazione IRCCS Policlinico San Matteo, P.le Golgi 19, I-27100 Pavia, Italy. Fax: ⫹39 0382 502618. E-mail: [email protected] (Received 20 January 2014; accepted 6 April 2014)
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Follow-up of coeliac disease 431 either in our unit or in other hospitals. As far as the patients diagnosed in our unit are concerned, to guarantee good quality samples, since 1999 we routinely take four duodenal biopsies in the second part of the duodenum during an upper endoscopy performed under mild sedation (midazolam 0.5 mg/kg i.v.). Biopsies are always oriented on cellulose nitrate paper, formalin-fixed and paraffin-embedded, and cut perpendicularly with respect to the luminal surface. Haematoxylin-eosin staining and CD3 immunohistochemical staining are routinely performed (6). Patients undergoing duodenal biopsies at our centre are always tested for endomysial antibodies (EMA) the same morning. IgA EMA were detected on monkey oesophagus/jejunum sections using an indirect immunofluorescence kit (The Binding Site, Birmingham, UK). In our hands, both sensitivity and specificity of EMA and tissue transglutaminase antibodies are very similar and satisfactory, as previously described (7). Finally, we always measure total IgA, IgG, and IgM to exclude IgA deficiency or hypogammaglobulinaemia. Patients diagnosed in other hospitals attended our out-patient clinic to confirm the diagnosis and provide them with gluten-free food certificates and regional health service tax exemption, as previously described (8). Patients with already diagnosed complicated CD, potential CD, CD diagnosed in childhood, and CD patients on a GFD for fewer than 12 months were excluded. Table I shows the data we collected and how they were standardized to be statistically analysed. We also collected date of diagnosis of CD, date of histological re-evaluation, and date of the last time the patient attended our out-patient clinic.
Statistical analysis Correspondence among serological data, clinical response, and diet adherence with histological findings, taken as gold standard (i.e. sensitivity and specificity), was analysed with 2 ⫻ 2 contingency tables, and differences were statistically valuated by chi-square test (9). A multivariate logistic regression was performed for discrimination purposes assuming the histological finding as dependent variable and the concomitant clinical data as predictive variables (9). Finally, a curve of the cumulative duration of the follow-up was calculated by means of the Kaplan– Meier method for those patients who underwent the histological re-evaluation (10).
Ethics Although all the patients signed informed consent before the biopsies, they could not be asked to consent specifically for this study because of its retrospective nature. Since many patients were lost to follow-up, after verifying the good quality of the data, the data were all irreversibly anonymized. The study was approved by the ethics committee of the Fondazione IRCCS Policlinico San Matteo according to the 1975 Declaration of Helsinki (6th revision, 2008).
Results Data from 446 adult coeliac patients were collected and included in the study: 254 of them were diagnosed directly in our unit, and the remaining 192 CD patients were diagnosed in other hospitals. After a median of 17 months (13–30 months, 25th–75th IQR), 317 patients (236 F, age at diagnosis of CD 33.1 ⫾ 12.1 years) received a complete re-evaluation consisting of clinical, serological, and histological examinations. The remaining 129 patients (90 F, age at diagnosis of CD 32.1 ⫾ 13.7 years) were not reinvestigated so thoroughly and were considered to be lost to follow-up for the purposes of this study.
Table I. Clinical and demographic data collected in all coeliac patients. Patients, n Sex Male Female Diagnosis of CD made in Our unit in Pavia Other hospital Clinical type of CD at diagnosis Classical/major Non-classical/minor Asymptomatic/silent EMA/TTA at diagnosis Positive Negative Duodenal histology at diagnosis Atrophy (Corazza–Villanacci B1–B2, Marsh–Oberhuber 3a/3c) Preatrophic/infiltrative (Corazza–Villanacci A, Marsh–Oberhuber 1/0) Normal Endoscopy complications at diagnosis No Yes Clinical picture at histological follow-up Persistent well-beingb Complete recoveryc Partial improvementd No significant improvemente Gluten-free diet adherencef Good Poor EMA at histological follow-up Positive Negative Endoscopy complications at histological follow-up Yes No Persistence of villous atrophy at histological follow-up Yes No
81 236 254 192 170 111 36 316 1 317 0a 0a 317 0 34 190 62 31 258 59 78 242 0 317 25 292
CD, coeliac disease; EMA, endomysial antibodies; TTA, tissue transglutaminase antibodies. aIt should be noted that patients with potential coeliac disease were excluded (see Methods). bAsymptomatic patient at diagnosis. cComplete resolution of all the symptoms, laboratory alterations, and nutritional deficiencies present at time of diagnosis of coeliac disease. dOnly partial improvement of symptoms, laboratory alterations, and nutritional deficiencies present at diagnosis. eNo significant improvement of symptoms, laboratory alterations, and nutritional deficiencies. fEvaluation based on a dietary interview performed by expert personnel.
Frank and satisfactory histological improvement (from Corazza–Villanacci B2/B1 to Corazza–Villanacci A/normal (11); from Marsh–Oberhuber 3c/3a to Marsh–Oberhuber 1/0) was found in 292 patients out of 317; in the remaining 25 patients (8%) histological response had been considered to be unsatisfactory because of the persistence of frank villous atrophy, and a third duodenal biopsy had been taken. EMA were still positive in 76 patients (24%), and GFD adherence and clinical response were unsatisfactory in 58 (18%) and 97 (31%) respectively. Although the P values of the contingency tables with clinical variables and histological findings were statistically significant (Table II), from a clinical point of view sensitivity and specificity were very disappointing and could not have been used to predict unsatisfactory histological response. A multivariate logistic analysis utilizing the data of EMA, GFD adherence, and clinical response was unable to foresee histological diagnosis with sufficient accuracy. As far as the 25 patients with unsatisfactory histological response are concerned, a third duodenal biopsy and further
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Table II. Sensitivity and specificity of serological response, GFD adherence, and clinical response, correlated with histological response, assumed as gold standard. Although P values for chi-square analyses were statistically significant, from a clinical point of view they were very disappointing. Positive endomysial antibodies Unsatisfactory GFD adherence Unsatisfactory clinical response
Sensitivity
Specificity
P value
48% 64% 56%
71% 80% 85%
⬍ 0.001 ⬍ 0.001 ⬍ 0.001
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GFD, gluten-free diet.
investigations, including demonstration of TCR-γ chain monoclonal rearrangements of intraepithelial T lymphocytes, allowed the diagnosis of refractory CD type 2 in one patient; four patients were deliberately consuming gluten, three are currently under investigations, and in the remaining patients a dietary re-evaluation suggested possible inadvertent gluten intake. However, in 10 patients the possibility of inadvertent gluten intake was so small that ‘slow responder CD’ was also possible. Figure 1 shows how many of the 317 patients who received a histological re-evaluation attended our out-patients clinic also in the following years (median follow-up time after diagnosis of CD 41 months, 88–21 months 25th–75th IQR). Clinical and demographic characteristics of patients lost to follow-up did not differ from those of the patients receiving follow-up. No correlation was found between persistence of villous atrophy at follow-up biopsy and the other parameters shown in Table I. Finally, no complication was recorded in any of the 788 upper endoscopies performed in this set of patients, at diagnosis and histological re-evaluation.
Discussion It is nowadays clear that coeliac patients require a follow-up (2–5). In some cases, follow-up modalities and timing are determined by good clinical practice. Patients diagnosed after the age of 50 years and/or because of classical/major symptoms of malabsorption are at an increased risk of complications and so they need to be followed up more strictly and thoroughly than patients diagnosed at a younger age and/or because of nonclassical/minor symptoms. Again, coeliac patients in whom severe symptoms of malabsorption persist or reoccur despite a strict GFD need to undergo thorough investigations to rule out the major complications of CD. However, despite these specific cases guided by the criteria of good clinical practice, it is still
Figure 1. Kaplan–Meier analysis for cumulative follow-up for the 317 patients who underwent histological re-evaluation calculated from time of diagnosis of coeliac disease until the last time the patient attended our clinic.
unclear how and when the majority of coeliac patients need to be followed up, and it has recently been stated that coeliac patients are not followed adequately (12). Some centres follow up coeliac patients on the basis of serological and clinical response, parameters that are very simple and cheap to evaluate. These methods are also very effective for the vast majority of patients, and some studies showed good correlation between mucosal recovery and levels of coeliac antibodies (13,14). Clinical re-evaluation is obviously of paramount importance, and a good clinical response has long been recognized to be of great relevance. However, 50% of the patients described in the present study were diagnosed because of familiarity or associated autoimmune conditions, without classical symptoms. The high number of coeliac patients not complaining of classical symptoms is a well-known issue, and it is obviously very difficult, if not impossible, to follow them up with clinical criteria (15). Evaluation of the compliance to a GFD is another very important aspect in the follow-up of CD patients. The gold standard for the evaluation of the strictness of a GFD is, however, represented by a dietary interview performed by an expert dietician (16), a procedure available only in referral centres. Only very recently have structured short surveys been developed for assessment of adherence to a GFD (17,18). Despite the widespread use of these non-invasive tools to follow up coeliac patients, it was, however, shown that seroconversion and clinical improvement after GFD do not necessarily imply healing of the intestinal mucosa (19–23). So, in some centres, a histological re-evaluation, the only reliable method to evaluate mucosal response (24–26), is also suggested. Although duodenal biopsy is an expensive and potentially hazardous procedure, our results show that a satisfactory histological improvement did not occur in 8% of the coeliac patients on a GFD for 12–18 months; in one of these 25 patients, refractory CD type 2 developed. If we had performed duodenal biopsies only in those patients with unsatisfactory clinical or serological response, the low sensitivities shown in Table II clearly indicate that only ∼50% of these CD patients without histological improvement would have been identified. If we keep in mind the high prevalence of CD in the general population and the role of a good histological response in preventing the complications of CD (26,27), the importance of this finding cannot be underestimated. Moreover, if we had performed a histological re-evaluation only in the coeliac patients with an unsatisfactory result at the non-invasive re-evaluations, the low specificities shown in Table II indicate that between 20% and 33% of all the coeliac patients would have nevertheless undergone a second duodenal biopsy. However, we must keep in mind that 129 patients (∼30%) were lost to follow-up. Since it may be assumed that the patients that do not seek medical follow-up are more likely to have had a good response to dietary treatment, this loss may have caused an underestimation of a satisfactory histological response in this study. Although the percentage of CD patients who receive followup is unknown (4), we noted that, overall, one patient out of four was lost to follow-up just after the diagnosis of CD. It is possible that at least some of the 192 patients diagnosed in other hospitals, and in whom we had only confirmed the diagnosis, returned to the original centres and were followed up there. However, it is theoretically possible that at least some of them were lost because they did not want to undergo a second duodenal biopsy, an unpleasant and theoretically hazardous procedure. Despite this, we must note that no complication occurred in any of the 788 endoscopies performed. Avoiding an upper endoscopy in a coeliac patient seems therefore to be much more dangerous than performing it.
Follow-up of coeliac disease 433 Due to its retrospective nature, our study was hindered by inevitable difficulties in data collection and thus by the high number of patients lost to follow-up. These problems could be resolved by a prospective study. However, the results of Table II are so disappointing that they are very unlikely to be improved by a prospective study. On the basis of our results, on those similar from another group (28), and on the disappointing correspondence between clinical, serological, and histological response to a GFD, (5,20–22,29), we conclude that a duodenal biopsy is necessary in the follow-up of adult coeliac patients.
Acknowledgements
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We are grateful to Susan West for reading and correcting the manuscript. Declaration of interest: The authors report no conflicts of interest.
References 1. Biagi F, Gobbi P, Marchese A, Borsotti E, Zingone F, Ciacci C, et al. Low incidence but poor prognosis of complicated coeliac disease: a retrospective multicentre study. Dig Liver Dis. 2014;46:227–30. 2. Howdle PD, Losowsky MS. Coeliac disease in adults. In: Marsh MN, editor. Coeliac disease. Oxford, UK: Blackwell; 1992. p. 49–80. 3. Rostom A, Murray JA, Kagnoff MF. American Gastroenterological Association (AGA) Institute technical review on the diagnosis and management of celiac disease. Gastroenterology. 2006;131:1981–2002. 4. 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. 5. Nasr I, Leffler DA, Ciclitira PJ. Management of celiac disease. Gastrointest Endoscopy Clin N Am. 2012;22:695–704. 6. Biagi F, Bianchi PI, Campanella J, Badulli C, Martinetti M, Klersy C, et al. The prevalence and the causes of minimal intestinal lesions in patients complaining of symptoms suggestive of enteropathy. A follow-up study. J Clin Pathol. 2008;61:1116–18. 7. Biagi F, Pezzimenti D, Campanella J, Vadacca GB, Corazza GR. Endomysial and tissue transglutaminase antibodies in coeliac sera. A comparison not influenced by previous serological testing. Scand J Gastroenterol. 2001;36:955–8. 8. Biagi F, Bianchi PI, Campanella J, Zanellati G, Corazza GR. The impact of misdiagnosing celiac disease at a referral centre. Can J Gastroenterol. 2009;23:543–5. 9. Armitage P, Berry G. Statistical methods in medical research. 2nd ed. Oxford, UK: Blackwell Scientific Publications; 1987. p. 127–9, 334–41. 10. Kaplan EL, Meier P. Non parametric estimation from incomplete observations. J Am Stat Assoc. 1958;53:457–81.
11. Corazza GR, Villanacci V. Coeliac disease. J Clin Pathol. 2005; 58:573–4. 12. Herman ML, Rubio-Tapia A, Lahr BD, Larson JJ, Van Dyke CT, Murray JA. Patients with celiac disease are not followed up adequately. Clin Gastroenterol Hepatol. 2012;10:893–9. 13. Pietzak MM. Follow-up of patients with celiac disease: achieving compliance with treatment. Gastroenterology. 2005;128:S135–41. 14. Dipper CR, Maitra S, Thomas R, Lamb CA, McLean-Tooke AP, Ward R, et al. Anti-tissue transglutaminase antibodies in the follow up of adult coeliac disease. Aliment Pharmacol Ther. 2009;30:236–44. 15. Rampertab SD, Pooran N, Brar P, Singh P, Green PH. Trends in the presentation of celiac disease. Am J Med. 2006;119:355.e9–14. 16. Case S. The gluten-free diet: how to provide effective education and resources. Gastroenterology. 2005;128:S128–34. 17. Biagi F, Bianchi PI, Marchese A, Trotta L, Vattiato C, Balduzzi D, et al. A score that verifies adherence to a gluten-free diet: a crosssectional, multicentre validation in real clinical life. Br J Nutr. 2012;108:1884–8. 18. Leffler DA, Dennis M, Edwards George JB, Jamma S, Magge S, Cook EF, et al. A simple validated gluten-free diet adherence survey for adults with celiac disease. Clin Gastroenterol Hepatol. 2009;7:530–6. 19. Rubio-Tapia A, Rahim MW, See JA, Lahr BD, Wu TT, Murray JA. Mucosal recovery and mortality in adults with celiac disease after treatment with a gluten-free diet. Am J Gastroenterol. 2010;105:1412–20. 20. Kaukinen K, Sulkanen S, Maki M, Collin P. IgA-class transglutaminase antibodies in evaluating the efficacy of gluten-free diet in coeliac disease. Eur J Gastroenterol Hepatol. 2002;14:311–15. 21. Troncone R, Mayer M, Spagnuolo F, Maiuri L, Greco L. Endomysial antibodies as unreliable marker for slight dietary transgressions in adolescents with coeliac disease. J Pediatr Gastroenterol Nutr. 1995; 21:69–72. 22. Dickey W, Hughes DF, McMillan SA. Disappearance of endomysial antibodies in treated celiac disease does not indicate histological recovery. Am J Gastroenterol. 2000;95:712–14. 23. Biagi F, Campanella J, Martucci S, Pezzimenti D, Ciclitira PJ, Ellis HJ, et al. A milligram of gluten a day keeps the mucosal recovery away. Nutr Rev. 2004;62:360–3. 24. Silvester JA, Rashid M. Long-term follow up of individuals with celiac disease: an evaluation of current practice guideline. Can J Gastroenterol. 2007;21:557–64. 25. Haines ML, Anderson RP, Gibson PR. Systematic review: the evidence base for long-term management of coeliac disease. Aliment Pharmacol Ther. 2008;1042–66. 26. Bardella MT, Velio P, Cesana BM, Prampolini L, Casella G, Di Bella C, et al. Coeliac disease: a histological follow-up study. Histopathology. 2007;50:465–71. 27. Elfström P, Granath F, Ekström Smedby K, Montgomery SM, Askling J, Ekbom A, et al. Risk of lymphoproliferative malignancy in relation to small intestinal histopathology among patients with celiac disease. J Natl Cancer Inst. 2011;103:436–44. 28. Hære P, Høie O, Schulz TB, Lundin KEA. Mucosal healing in Norwegian celiac patients. Abstract book 15th International Celiac Disease Symposium; Chicago 2013;8:I909, 22–25 September 2013. 29. Hutchinson JM, West NP, Robins GG, Howdle PD. Long-term histological follow up with coeliac disease in a UK teaching hospital. QJM. 2010;103:511–17.
ORIGINAL ARTICLE
A second duodenal biopsy is necessary in the follow-up of adult coeliac patients Federico Biagi, Claudia Vattiato, Simona Agazzi, Davide Balduzzi, Annalisa Schiepatti, Paolo Gobbi & Gino Roberto Corazza
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Coeliac Centre/First Department of Internal Medicine, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Italy
Introduction. Coeliac disease is a chronic enteropathy requiring a close follow-up. However, the best way to follow up coeliac patients has not yet been established. In the last 14 years, we have been offering patients a thorough series of periodical examinations including a histological re-evaluation at 12–18 months. Patients and methods. The notes of all coeliac patients attending our clinic between September 1999 and March 2013 were examined. Results. Data from 317 adult patients were collected. Duodenal biopsy showed a lack of satisfactory histological response in 25/317 patients; endomysial antibodies were still positive in 76, and diet adherence and clinical response were unsatisfactory in 58 and 97, respectively. Correlations of serological data, clinical response, and diet adherence with histological findings were evaluated. Although the P values showed statistically significant differences, sensitivity and specificity were disappointing: 64% and 80% for serological response, 48% and 71% for clinical response, 56% and 85% for diet adherence. Conclusions. After 12–18 months on a gluten-free diet, 8% of the patients do not present a satisfactory histological response; only some of them could have been identified with a serological and/ or clinical re-evaluation. Therefore, a duodenal biopsy seems to be the only tool that could identify patients with unsatisfactory histological response. Key words: Celiac disease, complications, endomysial antibodies, follow-up, gluten-free diet
Key messages • The need for a regular follow-up of coeliac patients is unquestionable. However, a consensus on timing and methods to follow up coeliac patients is at present still lacking. • Histological response was unsatisfactory in 8% of the coeliac patients on a gluten-free diet. • Clinical and serological response could not have been used to predict unsatisfactory histological response. A duodenal biopsy is necessary in the follow-up of adult coeliac patients.
unquestionable. This was already recognized in the early 1990s and confirmed repeatedly in the following years (2–4). In spite of this, a consensus on timing and methods to follow up coeliac patients is at present still lacking. Not only do different centres follow up coeliac patients with different methods and different timing, but it has also not been clarified whether CD patients should be followed up by general practitioners, gastroenterologists, or dieticians (4,5). In the last 14 years, we have been offering coeliac patients attending our unit a thorough series of periodical clinical and serological examinations which include a histological re-evaluation at 12–18 months. The aim of the present study is, therefore, to analyse the data we retrospectively collected in order to establish the best method to follow up coeliac patients.
Introduction Coeliac disease (CD) is a gluten-dependent enteropathy characterized by the need for a gluten-free diet (GFD). Providing that a strict and life-long GFD is maintained, the prognosis is excellent in the vast majority of patients. To start and maintain a strict GFD is, however, difficult, and patients need to be educated and regularly followed up. Another reason for checking coeliac patients periodically is the increased mortality of this condition, mainly due to its complications that can occur even after several years (1). The need for a regular follow-up is therefore
Patients and methods Data collection The clinical notes of all the patients affected by CD on a GFD attending our clinic between September 1999 and March 2013 were examined. All the patients had been diagnosed on the basis of an upper gastrointestinal endoscopy with duodenal biopsies showing frank villous atrophy and positive endomysial or tissue transglutaminase antibodies. These investigations were performed
Correspondence: Dr Federico Biagi, Coeliac Centre/1st Department of Internal Medicine, Fondazione IRCCS Policlinico San Matteo, P.le Golgi 19, I-27100 Pavia, Italy. Fax: ⫹39 0382 502618. E-mail: [email protected] (Received 20 January 2014; accepted 6 April 2014)
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Follow-up of coeliac disease 431 either in our unit or in other hospitals. As far as the patients diagnosed in our unit are concerned, to guarantee good quality samples, since 1999 we routinely take four duodenal biopsies in the second part of the duodenum during an upper endoscopy performed under mild sedation (midazolam 0.5 mg/kg i.v.). Biopsies are always oriented on cellulose nitrate paper, formalin-fixed and paraffin-embedded, and cut perpendicularly with respect to the luminal surface. Haematoxylin-eosin staining and CD3 immunohistochemical staining are routinely performed (6). Patients undergoing duodenal biopsies at our centre are always tested for endomysial antibodies (EMA) the same morning. IgA EMA were detected on monkey oesophagus/jejunum sections using an indirect immunofluorescence kit (The Binding Site, Birmingham, UK). In our hands, both sensitivity and specificity of EMA and tissue transglutaminase antibodies are very similar and satisfactory, as previously described (7). Finally, we always measure total IgA, IgG, and IgM to exclude IgA deficiency or hypogammaglobulinaemia. Patients diagnosed in other hospitals attended our out-patient clinic to confirm the diagnosis and provide them with gluten-free food certificates and regional health service tax exemption, as previously described (8). Patients with already diagnosed complicated CD, potential CD, CD diagnosed in childhood, and CD patients on a GFD for fewer than 12 months were excluded. Table I shows the data we collected and how they were standardized to be statistically analysed. We also collected date of diagnosis of CD, date of histological re-evaluation, and date of the last time the patient attended our out-patient clinic.
Statistical analysis Correspondence among serological data, clinical response, and diet adherence with histological findings, taken as gold standard (i.e. sensitivity and specificity), was analysed with 2 ⫻ 2 contingency tables, and differences were statistically valuated by chi-square test (9). A multivariate logistic regression was performed for discrimination purposes assuming the histological finding as dependent variable and the concomitant clinical data as predictive variables (9). Finally, a curve of the cumulative duration of the follow-up was calculated by means of the Kaplan– Meier method for those patients who underwent the histological re-evaluation (10).
Ethics Although all the patients signed informed consent before the biopsies, they could not be asked to consent specifically for this study because of its retrospective nature. Since many patients were lost to follow-up, after verifying the good quality of the data, the data were all irreversibly anonymized. The study was approved by the ethics committee of the Fondazione IRCCS Policlinico San Matteo according to the 1975 Declaration of Helsinki (6th revision, 2008).
Results Data from 446 adult coeliac patients were collected and included in the study: 254 of them were diagnosed directly in our unit, and the remaining 192 CD patients were diagnosed in other hospitals. After a median of 17 months (13–30 months, 25th–75th IQR), 317 patients (236 F, age at diagnosis of CD 33.1 ⫾ 12.1 years) received a complete re-evaluation consisting of clinical, serological, and histological examinations. The remaining 129 patients (90 F, age at diagnosis of CD 32.1 ⫾ 13.7 years) were not reinvestigated so thoroughly and were considered to be lost to follow-up for the purposes of this study.
Table I. Clinical and demographic data collected in all coeliac patients. Patients, n Sex Male Female Diagnosis of CD made in Our unit in Pavia Other hospital Clinical type of CD at diagnosis Classical/major Non-classical/minor Asymptomatic/silent EMA/TTA at diagnosis Positive Negative Duodenal histology at diagnosis Atrophy (Corazza–Villanacci B1–B2, Marsh–Oberhuber 3a/3c) Preatrophic/infiltrative (Corazza–Villanacci A, Marsh–Oberhuber 1/0) Normal Endoscopy complications at diagnosis No Yes Clinical picture at histological follow-up Persistent well-beingb Complete recoveryc Partial improvementd No significant improvemente Gluten-free diet adherencef Good Poor EMA at histological follow-up Positive Negative Endoscopy complications at histological follow-up Yes No Persistence of villous atrophy at histological follow-up Yes No
81 236 254 192 170 111 36 316 1 317 0a 0a 317 0 34 190 62 31 258 59 78 242 0 317 25 292
CD, coeliac disease; EMA, endomysial antibodies; TTA, tissue transglutaminase antibodies. aIt should be noted that patients with potential coeliac disease were excluded (see Methods). bAsymptomatic patient at diagnosis. cComplete resolution of all the symptoms, laboratory alterations, and nutritional deficiencies present at time of diagnosis of coeliac disease. dOnly partial improvement of symptoms, laboratory alterations, and nutritional deficiencies present at diagnosis. eNo significant improvement of symptoms, laboratory alterations, and nutritional deficiencies. fEvaluation based on a dietary interview performed by expert personnel.
Frank and satisfactory histological improvement (from Corazza–Villanacci B2/B1 to Corazza–Villanacci A/normal (11); from Marsh–Oberhuber 3c/3a to Marsh–Oberhuber 1/0) was found in 292 patients out of 317; in the remaining 25 patients (8%) histological response had been considered to be unsatisfactory because of the persistence of frank villous atrophy, and a third duodenal biopsy had been taken. EMA were still positive in 76 patients (24%), and GFD adherence and clinical response were unsatisfactory in 58 (18%) and 97 (31%) respectively. Although the P values of the contingency tables with clinical variables and histological findings were statistically significant (Table II), from a clinical point of view sensitivity and specificity were very disappointing and could not have been used to predict unsatisfactory histological response. A multivariate logistic analysis utilizing the data of EMA, GFD adherence, and clinical response was unable to foresee histological diagnosis with sufficient accuracy. As far as the 25 patients with unsatisfactory histological response are concerned, a third duodenal biopsy and further
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Table II. Sensitivity and specificity of serological response, GFD adherence, and clinical response, correlated with histological response, assumed as gold standard. Although P values for chi-square analyses were statistically significant, from a clinical point of view they were very disappointing. Positive endomysial antibodies Unsatisfactory GFD adherence Unsatisfactory clinical response
Sensitivity
Specificity
P value
48% 64% 56%
71% 80% 85%
⬍ 0.001 ⬍ 0.001 ⬍ 0.001
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GFD, gluten-free diet.
investigations, including demonstration of TCR-γ chain monoclonal rearrangements of intraepithelial T lymphocytes, allowed the diagnosis of refractory CD type 2 in one patient; four patients were deliberately consuming gluten, three are currently under investigations, and in the remaining patients a dietary re-evaluation suggested possible inadvertent gluten intake. However, in 10 patients the possibility of inadvertent gluten intake was so small that ‘slow responder CD’ was also possible. Figure 1 shows how many of the 317 patients who received a histological re-evaluation attended our out-patients clinic also in the following years (median follow-up time after diagnosis of CD 41 months, 88–21 months 25th–75th IQR). Clinical and demographic characteristics of patients lost to follow-up did not differ from those of the patients receiving follow-up. No correlation was found between persistence of villous atrophy at follow-up biopsy and the other parameters shown in Table I. Finally, no complication was recorded in any of the 788 upper endoscopies performed in this set of patients, at diagnosis and histological re-evaluation.
Discussion It is nowadays clear that coeliac patients require a follow-up (2–5). In some cases, follow-up modalities and timing are determined by good clinical practice. Patients diagnosed after the age of 50 years and/or because of classical/major symptoms of malabsorption are at an increased risk of complications and so they need to be followed up more strictly and thoroughly than patients diagnosed at a younger age and/or because of nonclassical/minor symptoms. Again, coeliac patients in whom severe symptoms of malabsorption persist or reoccur despite a strict GFD need to undergo thorough investigations to rule out the major complications of CD. However, despite these specific cases guided by the criteria of good clinical practice, it is still
Figure 1. Kaplan–Meier analysis for cumulative follow-up for the 317 patients who underwent histological re-evaluation calculated from time of diagnosis of coeliac disease until the last time the patient attended our clinic.
unclear how and when the majority of coeliac patients need to be followed up, and it has recently been stated that coeliac patients are not followed adequately (12). Some centres follow up coeliac patients on the basis of serological and clinical response, parameters that are very simple and cheap to evaluate. These methods are also very effective for the vast majority of patients, and some studies showed good correlation between mucosal recovery and levels of coeliac antibodies (13,14). Clinical re-evaluation is obviously of paramount importance, and a good clinical response has long been recognized to be of great relevance. However, 50% of the patients described in the present study were diagnosed because of familiarity or associated autoimmune conditions, without classical symptoms. The high number of coeliac patients not complaining of classical symptoms is a well-known issue, and it is obviously very difficult, if not impossible, to follow them up with clinical criteria (15). Evaluation of the compliance to a GFD is another very important aspect in the follow-up of CD patients. The gold standard for the evaluation of the strictness of a GFD is, however, represented by a dietary interview performed by an expert dietician (16), a procedure available only in referral centres. Only very recently have structured short surveys been developed for assessment of adherence to a GFD (17,18). Despite the widespread use of these non-invasive tools to follow up coeliac patients, it was, however, shown that seroconversion and clinical improvement after GFD do not necessarily imply healing of the intestinal mucosa (19–23). So, in some centres, a histological re-evaluation, the only reliable method to evaluate mucosal response (24–26), is also suggested. Although duodenal biopsy is an expensive and potentially hazardous procedure, our results show that a satisfactory histological improvement did not occur in 8% of the coeliac patients on a GFD for 12–18 months; in one of these 25 patients, refractory CD type 2 developed. If we had performed duodenal biopsies only in those patients with unsatisfactory clinical or serological response, the low sensitivities shown in Table II clearly indicate that only ∼50% of these CD patients without histological improvement would have been identified. If we keep in mind the high prevalence of CD in the general population and the role of a good histological response in preventing the complications of CD (26,27), the importance of this finding cannot be underestimated. Moreover, if we had performed a histological re-evaluation only in the coeliac patients with an unsatisfactory result at the non-invasive re-evaluations, the low specificities shown in Table II indicate that between 20% and 33% of all the coeliac patients would have nevertheless undergone a second duodenal biopsy. However, we must keep in mind that 129 patients (∼30%) were lost to follow-up. Since it may be assumed that the patients that do not seek medical follow-up are more likely to have had a good response to dietary treatment, this loss may have caused an underestimation of a satisfactory histological response in this study. Although the percentage of CD patients who receive followup is unknown (4), we noted that, overall, one patient out of four was lost to follow-up just after the diagnosis of CD. It is possible that at least some of the 192 patients diagnosed in other hospitals, and in whom we had only confirmed the diagnosis, returned to the original centres and were followed up there. However, it is theoretically possible that at least some of them were lost because they did not want to undergo a second duodenal biopsy, an unpleasant and theoretically hazardous procedure. Despite this, we must note that no complication occurred in any of the 788 endoscopies performed. Avoiding an upper endoscopy in a coeliac patient seems therefore to be much more dangerous than performing it.
Follow-up of coeliac disease 433 Due to its retrospective nature, our study was hindered by inevitable difficulties in data collection and thus by the high number of patients lost to follow-up. These problems could be resolved by a prospective study. However, the results of Table II are so disappointing that they are very unlikely to be improved by a prospective study. On the basis of our results, on those similar from another group (28), and on the disappointing correspondence between clinical, serological, and histological response to a GFD, (5,20–22,29), we conclude that a duodenal biopsy is necessary in the follow-up of adult coeliac patients.
Acknowledgements
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We are grateful to Susan West for reading and correcting the manuscript. Declaration of interest: The authors report no conflicts of interest.
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