Case report 679
Prudence is necessary in the application of the new ESPGHAN criteria for celiac disease omitting duodenal biopsy: a case report Enrico Schirrua, Rita-De´sire´e Joresc and Mauro Congiab New guidelines for celiac disease (CD) diagnosis from the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) propose the option to omit the duodenal biopsy in the diagnosis of CD. For this option, all four of the following criteria have to apply in children and adolescents: signs and symptoms suggestive of CD, anti-transglutaminase type 2 antibody (anti-TG2) levels more than 10 times the upper limit of normal, positive confirmation tests of anti-endomysium-IgA antibodies (EMA), and at-risk HLA-DQ2 or HLA-DQ8. Here, we report the case of a female patient, 2 years old, with chronic diarrhea that started after an acute viral gastroenteritis. The patient had anti-TG2 levels of more than 10 times the upper limit of normal, positivity for EMA, antigliadin IgA, and IgG (AGA-IgA, AGA-IgG, respectively), and the at-risk HLA-DRB1*0301, DQB1*0201/DRB1*10, DQB1*0501 genotype, thus fulfilling all criteria for the diagnosis of CD. Although the diarrhea disappeared after about 5 weeks, anti-TG2, EMA, and AGA-IgG remained positive. Therefore, a duodenal biopsy was performed and evidenced a normal mucosa (Marsh 0). After about 18 months, the antibody titer for AGA-IgG, anti-TG2,
Introduction Celiac disease (CD) is an immune-mediated systemic disease triggered and maintained by dietary gluten in genetically predisposed individuals, characterized by a variable degree of intestinal villous damage and by a variable combination of clinical manifestations [1]. Recently, a working group within the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) has formulated new guidelines for CD diagnosis that offer the option to omit the intestinal biopsy in children and adolescents [1]. The requirements are as follows: symptoms and signs suggestive of CD, antitransglutaminase type 2 antibody (anti-TG2) levels of more than 10 times the upper limit of normal, positive confirmation tests of anti-endomysium-IgA antibodies (EMA), and presence of at-risk HLA-DQ2 or HLA-DQ8. If all requirements are fulfilled, the diagnosis of CD is made, a gluten-free diet is started, and the patient is followed for improvement in symptoms and decrease of autoantibodies [1]. A later gluten challenge in these patients is not required [1]. In this paper, we report a unique case that suggests the introduction of a waiting period with repetition of c 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins 0954-691X
and EMA became negative. The patient was all the time on a normal, gluten-containing diet. This clinical case represents an exception to the new ESPGHAN guidelines for CD diagnosis. During 5 weeks, the new ESPGHAN criteria were all fulfilled, allowing to propose for this patient the diagnosis of CD without performing a duodenal biopsy. Therefore, a prudent approach is suggested when the pediatric gastroenterologist makes a diagnosis of CD without duodenal biopsy. Eur J Gastroenterol Hepatol c 2014 Wolters Kluwer Health | Lippincott 26:679–680 Williams & Wilkins. European Journal of Gastroenterology & Hepatology 2014, 26:679–680 Keywords: celiac disease, duodenal biopsy, Paediatric Gastroenterology, Hepatology, and Nutrition a Department of Public Health, Clinical & Molecular Medicine, University of Cagliari, University Campus, bUnit of Gastroenterology, Microcitemico Hospital, Cagliari and cASL8 Cagliari, Blood Donation Center, Quartu Sant’Elena, Italy
Correspondence to Mauro Congia, MD, Unit of Gastroenterology, Microcitemico Hospital, ASL8, Cagliari, Via Jenner, 09121, Cagliari, Italy Tel: + 39 070 609 5522; fax: + 39 070 609 5656; e-mail: [email protected] Received 14 January 2014 Accepted 5 March 2014
serology before diagnosis, which can avoid a false diagnosis following these new ESPGHAN guidelines.
Case report A 2-year-old female patient came to our hospital at the end of February 2012 presenting with chronic diarrhea since 34 days, which started after an acute viral gastroenteritis associated with vomiting and fever that lasted 2 days. Because of the persistence of diarrhea, the general practitioner had prescribed several laboratory tests including a screening for CD: anti-TG2, EMA, antigliadin IgA, and IgG (AGA-IgA, AGA-IgG, respectively). All of them were positive, with the exception of the AGA-IgA (Table 1). As symptoms and serology were positive, HLA typing was requested to complete the requirements of the new ESPGHAN criteria. The DRB1*0301, DQB1*0201/DRB1*10, DQB1*0501 genotype carrying the CD-associated susceptible HLA-DQ2.5 heterodimer was found. In the next hematological control in March 2012, a reduction in the anti-TG2 level was observed from 130 to 100 U/ml (a value, however, >10 upper limit of normal). DOI: 10.1097/MEG.0000000000000096
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
680 European Journal of Gastroenterology & Hepatology 2014, Vol 26 No 6
Table 1
Patient clinical data, values of autoantibodies, and ESPGHAN criteria during 18 months of follow-up
EMA AGA-IgA AGA-IgG Anti-TG2 Symptoms ESPGHAN criteria
07/02/2012
15/03/2012
27/04/2012
10/09/2012
04/02/2013
10/07/2013
4 3.7 40.1 > 10 ULN Diarrhea Diagnosis of CD w/o OEGDB
4 1.3 30.1 > 10 ULN Diarrhea Diagnosis of CD w/o OEGDB
4 1 24.1 7 ULN No No
0 1.1 21.9 3 ULN No No
0 1.3 19.4 1 ULN No No
0 / / < 1 ULN No No
EMA were expressed as the intensity of immunofluorescence from 0 to 4. AGA-IgA and AGA-IgG were considered positive for values higher than 3 mg/l. Anti-TG2 were expressed in times the upper limit of normal with a cut-off of 7 U/ml. CD, celiac disease; EMA, anti-endomysium-IgA antibodies; ESPGHAN, European Society for Paediatric Gastroenterology, Hepatology, and Nutrition; OEGDB, esophagogastroduodenoscopy and biopsy; ULN, upper limit of normal; w/o, without.
As the new ESPGHAN criteria include symptoms of CD, but at this time point diarrhea had disappeared, a duodenal biopsy was requested as well as repetition of the serology (Table 1). The biopsy was performed in June. Histology indicated a normal mucosa (Marsh 0) [2,3]. Therefore, the diagnosis of potential CD was formulated and no gluten-free diet was administered [1,4]. During the following months, a further decrease in AGA-IgG and anti-TG2 was observed and EMA became negative in September 2012. The subsequent analyses (last control in July 2013) showed normalization of CD-associated antibodies (Table 1). However, a clinical control with anti-TG2 and EMA testing has been planned every year considering her peculiar clinical history and the presence of the CD-predisposing HLA-DRB1*0301, HLADQB1*0201 haplotype.
reports showing that infections or inflammatory diseases may produce false-positive anti-TG2 [5–7]. However, our patient also showed strong positive values of EMA, a finding not observed in patients with infectious diseases (pharyngitis and lymphadenopathy) [5]. Therefore, our study shows that, contrary to previous data, both antiTG2 and EMA values may be altered in the presence of gastrointestinal infections. Conclusion
Our findings suggest that it is more prudent, even with the fulfillment of all new ESPGHAN criteria, to wait several weeks and repeat the serology, several times if necessary, to avoid an unnecessary gluten-free diet in a non-CD patient with gastrointestinal infection.
Acknowledgements
A signed permission form with the informed consent to participate in the study was obtained from the patient’s parents.
Conflicts of interest
This clinical case represents an exception to the new ESPGHAN guidelines for CD diagnosis and suggests a prudent approach when the pediatric gastroenterologist makes a diagnosis of CD without duodenal biopsy [1]. Indeed, in February and part of March 2012, when the symptom of diarrhea was still present, the new ESPGHAN criteria were completely fulfilled, allowing to establish the diagnosis of CD for this patient without performing a duodenal biopsy.
References
However, as we also observed that diarrhea was decreasing and disappeared completely in March, a watch and wait strategy was adopted until June 2012, when the duodenal biopsy was performed, indicating a completely normal mucosa. A possible explanation of our finding is that the high antiTG2 was induced by the gastroenteritis in analogy to
There are no conflicts of interest.
1
2 3 4
5
6 7
Husby S, Koletzko S, Korponay-Szabo IR, Mearin ML, Phillips A, Shamir R, et al. European Society for Pediatric Gastroenterology, Hepatology, and Nutrition Guidelines for the Diagnosis of Coeliac Disease. J Pediatr Gastroenterol Nutr 2012; 54:136–160. Marsh MN, Crowe PT. Morphology of the mucosal lesion in gluten sensitivity. Baillieres Clin Gastroenterol 1995; 9:273–293. Oberhuber G. Histopathology of celiac disease. Biomed Pharmacother 2000; 54:368–372. Schirru E, Jores RD, Cicotto L, Frau F, De Virgiliis S, Rossino R, et al. High frequency of low-risk human leukocyte antigen class II genotypes in latent celiac disease. Hum Immunol 2011; 72:179–182. Ferrara F, Quaglia S, Caputo I, Esposito C, Lepretti M, Pastore S, et al. Antitransglutaminase antibodies in non-coeliac children suffering from infectious diseases. Clin Exp Immunol 2010; 159:217–223. Freeman HJ. Strongly positive tissue transglutaminase antibody assays without celiac disease. Can J Gastroenterol 2004; 18:25–28. Stene LC, Honeyman MC, Hoffenberg EJ, Haas JE, Sokol RJ, Emery L, et al. Rotavirus infection frequency and risk of celiac disease autoimmunity in early childhood: a longitudinal study. Am J Gastroenterol 2006; 101: 2333–2340.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Prudence is necessary in the application of the new ESPGHAN criteria for celiac disease omitting duodenal biopsy: a case report Enrico Schirrua, Rita-De´sire´e Joresc and Mauro Congiab New guidelines for celiac disease (CD) diagnosis from the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) propose the option to omit the duodenal biopsy in the diagnosis of CD. For this option, all four of the following criteria have to apply in children and adolescents: signs and symptoms suggestive of CD, anti-transglutaminase type 2 antibody (anti-TG2) levels more than 10 times the upper limit of normal, positive confirmation tests of anti-endomysium-IgA antibodies (EMA), and at-risk HLA-DQ2 or HLA-DQ8. Here, we report the case of a female patient, 2 years old, with chronic diarrhea that started after an acute viral gastroenteritis. The patient had anti-TG2 levels of more than 10 times the upper limit of normal, positivity for EMA, antigliadin IgA, and IgG (AGA-IgA, AGA-IgG, respectively), and the at-risk HLA-DRB1*0301, DQB1*0201/DRB1*10, DQB1*0501 genotype, thus fulfilling all criteria for the diagnosis of CD. Although the diarrhea disappeared after about 5 weeks, anti-TG2, EMA, and AGA-IgG remained positive. Therefore, a duodenal biopsy was performed and evidenced a normal mucosa (Marsh 0). After about 18 months, the antibody titer for AGA-IgG, anti-TG2,
Introduction Celiac disease (CD) is an immune-mediated systemic disease triggered and maintained by dietary gluten in genetically predisposed individuals, characterized by a variable degree of intestinal villous damage and by a variable combination of clinical manifestations [1]. Recently, a working group within the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) has formulated new guidelines for CD diagnosis that offer the option to omit the intestinal biopsy in children and adolescents [1]. The requirements are as follows: symptoms and signs suggestive of CD, antitransglutaminase type 2 antibody (anti-TG2) levels of more than 10 times the upper limit of normal, positive confirmation tests of anti-endomysium-IgA antibodies (EMA), and presence of at-risk HLA-DQ2 or HLA-DQ8. If all requirements are fulfilled, the diagnosis of CD is made, a gluten-free diet is started, and the patient is followed for improvement in symptoms and decrease of autoantibodies [1]. A later gluten challenge in these patients is not required [1]. In this paper, we report a unique case that suggests the introduction of a waiting period with repetition of c 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins 0954-691X
and EMA became negative. The patient was all the time on a normal, gluten-containing diet. This clinical case represents an exception to the new ESPGHAN guidelines for CD diagnosis. During 5 weeks, the new ESPGHAN criteria were all fulfilled, allowing to propose for this patient the diagnosis of CD without performing a duodenal biopsy. Therefore, a prudent approach is suggested when the pediatric gastroenterologist makes a diagnosis of CD without duodenal biopsy. Eur J Gastroenterol Hepatol c 2014 Wolters Kluwer Health | Lippincott 26:679–680 Williams & Wilkins. European Journal of Gastroenterology & Hepatology 2014, 26:679–680 Keywords: celiac disease, duodenal biopsy, Paediatric Gastroenterology, Hepatology, and Nutrition a Department of Public Health, Clinical & Molecular Medicine, University of Cagliari, University Campus, bUnit of Gastroenterology, Microcitemico Hospital, Cagliari and cASL8 Cagliari, Blood Donation Center, Quartu Sant’Elena, Italy
Correspondence to Mauro Congia, MD, Unit of Gastroenterology, Microcitemico Hospital, ASL8, Cagliari, Via Jenner, 09121, Cagliari, Italy Tel: + 39 070 609 5522; fax: + 39 070 609 5656; e-mail: [email protected] Received 14 January 2014 Accepted 5 March 2014
serology before diagnosis, which can avoid a false diagnosis following these new ESPGHAN guidelines.
Case report A 2-year-old female patient came to our hospital at the end of February 2012 presenting with chronic diarrhea since 34 days, which started after an acute viral gastroenteritis associated with vomiting and fever that lasted 2 days. Because of the persistence of diarrhea, the general practitioner had prescribed several laboratory tests including a screening for CD: anti-TG2, EMA, antigliadin IgA, and IgG (AGA-IgA, AGA-IgG, respectively). All of them were positive, with the exception of the AGA-IgA (Table 1). As symptoms and serology were positive, HLA typing was requested to complete the requirements of the new ESPGHAN criteria. The DRB1*0301, DQB1*0201/DRB1*10, DQB1*0501 genotype carrying the CD-associated susceptible HLA-DQ2.5 heterodimer was found. In the next hematological control in March 2012, a reduction in the anti-TG2 level was observed from 130 to 100 U/ml (a value, however, >10 upper limit of normal). DOI: 10.1097/MEG.0000000000000096
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
680 European Journal of Gastroenterology & Hepatology 2014, Vol 26 No 6
Table 1
Patient clinical data, values of autoantibodies, and ESPGHAN criteria during 18 months of follow-up
EMA AGA-IgA AGA-IgG Anti-TG2 Symptoms ESPGHAN criteria
07/02/2012
15/03/2012
27/04/2012
10/09/2012
04/02/2013
10/07/2013
4 3.7 40.1 > 10 ULN Diarrhea Diagnosis of CD w/o OEGDB
4 1.3 30.1 > 10 ULN Diarrhea Diagnosis of CD w/o OEGDB
4 1 24.1 7 ULN No No
0 1.1 21.9 3 ULN No No
0 1.3 19.4 1 ULN No No
0 / / < 1 ULN No No
EMA were expressed as the intensity of immunofluorescence from 0 to 4. AGA-IgA and AGA-IgG were considered positive for values higher than 3 mg/l. Anti-TG2 were expressed in times the upper limit of normal with a cut-off of 7 U/ml. CD, celiac disease; EMA, anti-endomysium-IgA antibodies; ESPGHAN, European Society for Paediatric Gastroenterology, Hepatology, and Nutrition; OEGDB, esophagogastroduodenoscopy and biopsy; ULN, upper limit of normal; w/o, without.
As the new ESPGHAN criteria include symptoms of CD, but at this time point diarrhea had disappeared, a duodenal biopsy was requested as well as repetition of the serology (Table 1). The biopsy was performed in June. Histology indicated a normal mucosa (Marsh 0) [2,3]. Therefore, the diagnosis of potential CD was formulated and no gluten-free diet was administered [1,4]. During the following months, a further decrease in AGA-IgG and anti-TG2 was observed and EMA became negative in September 2012. The subsequent analyses (last control in July 2013) showed normalization of CD-associated antibodies (Table 1). However, a clinical control with anti-TG2 and EMA testing has been planned every year considering her peculiar clinical history and the presence of the CD-predisposing HLA-DRB1*0301, HLADQB1*0201 haplotype.
reports showing that infections or inflammatory diseases may produce false-positive anti-TG2 [5–7]. However, our patient also showed strong positive values of EMA, a finding not observed in patients with infectious diseases (pharyngitis and lymphadenopathy) [5]. Therefore, our study shows that, contrary to previous data, both antiTG2 and EMA values may be altered in the presence of gastrointestinal infections. Conclusion
Our findings suggest that it is more prudent, even with the fulfillment of all new ESPGHAN criteria, to wait several weeks and repeat the serology, several times if necessary, to avoid an unnecessary gluten-free diet in a non-CD patient with gastrointestinal infection.
Acknowledgements
A signed permission form with the informed consent to participate in the study was obtained from the patient’s parents.
Conflicts of interest
This clinical case represents an exception to the new ESPGHAN guidelines for CD diagnosis and suggests a prudent approach when the pediatric gastroenterologist makes a diagnosis of CD without duodenal biopsy [1]. Indeed, in February and part of March 2012, when the symptom of diarrhea was still present, the new ESPGHAN criteria were completely fulfilled, allowing to establish the diagnosis of CD for this patient without performing a duodenal biopsy.
References
However, as we also observed that diarrhea was decreasing and disappeared completely in March, a watch and wait strategy was adopted until June 2012, when the duodenal biopsy was performed, indicating a completely normal mucosa. A possible explanation of our finding is that the high antiTG2 was induced by the gastroenteritis in analogy to
There are no conflicts of interest.
1
2 3 4
5
6 7
Husby S, Koletzko S, Korponay-Szabo IR, Mearin ML, Phillips A, Shamir R, et al. European Society for Pediatric Gastroenterology, Hepatology, and Nutrition Guidelines for the Diagnosis of Coeliac Disease. J Pediatr Gastroenterol Nutr 2012; 54:136–160. Marsh MN, Crowe PT. Morphology of the mucosal lesion in gluten sensitivity. Baillieres Clin Gastroenterol 1995; 9:273–293. Oberhuber G. Histopathology of celiac disease. Biomed Pharmacother 2000; 54:368–372. Schirru E, Jores RD, Cicotto L, Frau F, De Virgiliis S, Rossino R, et al. High frequency of low-risk human leukocyte antigen class II genotypes in latent celiac disease. Hum Immunol 2011; 72:179–182. Ferrara F, Quaglia S, Caputo I, Esposito C, Lepretti M, Pastore S, et al. Antitransglutaminase antibodies in non-coeliac children suffering from infectious diseases. Clin Exp Immunol 2010; 159:217–223. Freeman HJ. Strongly positive tissue transglutaminase antibody assays without celiac disease. Can J Gastroenterol 2004; 18:25–28. Stene LC, Honeyman MC, Hoffenberg EJ, Haas JE, Sokol RJ, Emery L, et al. Rotavirus infection frequency and risk of celiac disease autoimmunity in early childhood: a longitudinal study. Am J Gastroenterol 2006; 101: 2333–2340.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
