La enfermedad celíaca (EC) es una alteración sistémica de carácter autoinmune desencadenada por el consumo de gluten y prolaminas en individuos genéticamente predispuestos, que consiste en una combinación variable de manifestaciones clínicas gluten-dependientes, presencia de autoanticuerpos específicos, genética de riesgo HLA DQ2 o DQ8 y enteropatía¹.

La cascada patogénica se inicia en el intestino delgado, con un aumento de la permeabilidad intestinal a la gliadina del gluten y pérdida de tolerancia, generando una respuesta inmunológica innata y adaptativa de tipo humoral y celular, que se desencadena por un elemento externo, el gluten, tras ser deamidado por la transglutaminasa tisular de tipo 2 (TG2), que constituye el principal autoantígeno en la EC^2,3.

Gracias a las guías de la Sociedad Europea de Gastroenterología, Hepatología y Nutrición Pediátrica (ESPGHAN) publicadas en el año 2012¹, es posible, en edad pediátrica, realizar el diagnóstico sin biopsia, siempre que exista sintomatología evidente atribuible a EC activa, junto con marcadores antitransglutaminasa (ATG2) claramente positivos (> 10 veces el límite de normalidad) y antiendomisio (EMA) también positivo en una segunda determinación, junta a un genotipo HLA de riesgo (DQ2 o DQ8). Estas guías ponen de manifiesto dos aspectos importantes: el carácter sistémico de la enfermedad, donde la enteropatía es considerada un elemento más del diagnóstico, y la genética HLA de riesgo como factor necesario.

Sin embargo, su desarrollo y aplicabilidad no hubiera sido posible sin las herramientas serológicas actuales: ATG2 y EMA de tipo IgA, ambas contra el mismo antígeno (TG2). Puesto que la enteropatía ya no se considera imprescindible, los últimos avances se están dirigiendo a desarrollar y mejorar técnicas no invasivas y combinaciones de marcadores serológicos para el diagnóstico de la enfermedad.

Los anticuerpos contra la gliadina de tipo IgA (AGA) poseen una sensibilidad (S) elevada, pero también son detectados en individuos sanos y en individuos con otro tipo de enteropatía no celíaca. Sus títulos se correlacionan con la ingesta de gluten y se considera que su presencia forma parte de la respuesta inmunológica de la mucosa. Al aparecer los demás anticuerpos (EMA y ATG2) su uso es minoritario, quedando relegado a los niños menores de 2 años, en los que un 10% pueden no haber desarrollado ATG2 o EMA en el momento de la sospecha diagnóstica⁴.

La determinación de EMA es la prueba más específica (97-100%), con un valor predictivo positivo (VPP) de 98-100% para el diagnóstico de EC. Sin embargo, tiene una serie de inconvenientes técnicos que dificultan su realización en masa, como son el procesamiento manual y el que su interpretación es subjetiva. Al conseguir la detección de TG2 por ELISA, mucho más sencillo y con casi igual especificidad (E), su utilidad fundamental consiste en suplir los posibles falsos negativos de los ATG2^4,5 y confirmar en segunda muestra la positividad de ATG2 para evitar la biopsia según los nuevos criterios.

Los ATG2 actualmente son el marcador de elección porque si bien son algo menos específicos (S del 91-95% y E del 95-97%) que los EMA, son fácilmente realizables de forma rápida. Desde hace años se relaciona el título de ATG2 con el grado de daño histológico en la EC⁶, incluso que los títulos de anticuerpos son directamente proporcionales al tipo de lesión vellositaria. Los pacientes con ATG2 > 100 U/ml tienen al menos un grado de lesión Marsh 2, y posteriormente han aparecido estudios tanto prospectivos⁷ como retrospectivos^8-10, en los que la correlación es del 100% entre el título de ATG y el diagnóstico de EC confirmado por biopsia, de ahí que la ESPGHAN estableciese un límite mayor de 10 veces el valor de referencia para poder omitir la biopsia intestinal.

Posteriormente, se observó la elevada afinidad de los linfocitos T restringidos por HLA-DQ2/8 por los péptidos ya deamidados por la TG2, reacción que no ocurre en individuos sanos, y se implementó la técnica de análisis de péptidos deamidados de la gliadina (PDG), inicialmente detectados por ELISA, con una sensibilidad (S) entre 70-95% y especificidad (E) de 80-94% para los de tipo IgG. Son útiles en los casos en los que el rendimiento de los ATG2 puede ser menor, como menores de 2 años y déficit IgA, pero el valor predictivo positivo (VPP) de la prueba de forma aislada es bajo (30%), por lo que no se recomienda si no se determinan en combinación con ATG2 o EMA¹¹. Además, la ESPGHAN no contempla por el momento la positividad para anticuerpos PDG. En la última década se han comercializado unos kits rápidos en sangre capilar basados en la detección de PDG que son útiles como cribado inicial, que cuentan con elevada S y E, y con excelente VPN¹². Aun así, no son equiparables a los ATG 2 y EMA¹³, por lo que en caso positivo (o negativo con sospecha clínica fuerte) debería confirmarse con serología convencional.

Este año se han publicado dos estudios destacados con el objeto de evaluar la eficacia de la serología y la pertinencia de las nuevas guías de la ESPGHAN. El primero valora la eficacia de los marcadores ATG2 en solitario con títulos > 10 veces el valor de referencia como método diagnóstico fiable y que permite obviar la biopsia siempre que exista sintomatología¹⁴, aportando como objeción a las nuevas guías de la ESPGHAN el carácter prescindible del HLA, y el presente estudio de carácter prospectivo, valorado en el presente número de Evidencias en Pediatría, comparando marcadores ATG2 y la detección combinada de ATG2 y PDG¹⁵. En este último también refieren excelentes valores predictivos positivos y negativos para la detección combinada, aunque sin cubrir los posibles huecos que dejan los niveles intermedios a la hora de precisar biopsia en casos de EC seronegativa¹⁶, enfermedades asociadas y grupos de riesgo, y pacientes asintomáticos. Además, la fiabilidad de estos resultados se aplica a valores mínimos de prevalencia de 4%, por lo que no serían extrapolables a prevalencias bajas de la enfermedad en población general, como es el caso de nuestro medio, ni aceptables en pacientes asintomáticos, como concluyen los revisores del estudio¹⁷.

 Esta es una de las razones por las que la biopsia intestinal continúa considerándose el patrón oro para el diagnóstico en adultos o fuera de Europa¹⁸, tanto para niños como para adultos^19,20.

Bibliografía

1. Husby S, Koletzko S, Korponay-Szabó 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;54:136-60.
2. Kumar J, Kumar M, Pandey R, Chauhan NS. Physiopathology and Management of Gluten-Induced Celiac Disease. J Food Sci. 2017;82:270-7.
3. Koning F. Celiac disease: quantity matters. Semin Immunopathol. 2012;34:541-9.
4. Maglio M, Tosco A, Paparo F, Auricchio R, Granata V, Colicchio B, et al. Serum and intestinal celiac disease-associated antibodies in children with celiac disease younger than 2 years of age. J Pediatr Gastroenterol Nutr. 2010;50:43-8.
5. Giersiepen K, Lelgemann M, Stuhldreher N, Ronfani L, Husby S, Koletzko S, et al. Accuracy of diagnostic antibody tests for coeliac disease in children: summary of an evidence report. J Pediatr Gastroenterol Nutr. 2012;54:229-41.
6. Barker CC, Mitton C, Jevon G, Mock T. Can tissue transglutaminase antibody titers replace small-bowel biopsy to diagnose celiac disease in select pediatric populations? Pediatrics. 2005;115:1341-6.
7. Mubarak A, Wolters VM, Gmelig-Meyling FHJ, Ten Kate FJW, Houwen RHJ. Tissue transglutaminase levels above 100 U/mL and celiac disease: a prospective study. World J Gastroenterol. 2012;18:4399-403.
8. Donaldson MR, Book LS, Leiferman KM, Zone JJ, Neuhausen SL. Strongly positive tissue transglutaminase antibodies are associated with Marsh 3 histopathology in adult and pediatric celiac disease. J Clin Gastroenterol. 2008;42:256-60.
9. Alessio MG, Tonutti E, Brusca I, Radice A, Licini L, Sonzogni A, et al. Correlation between IgA tissue transglutaminase antibody ratio and histological finding in celiac disease. J Pediatr Gastroenterol Nutr. 2012;55:44-9.
10. Singh P, Kurray L, Agnihotri A, Das P, Verma AK, Sreenivas V, et al. Titers of anti-tissue transglutaminase antibody correlate well with severity of villous abnormalities in celiac disease. J Clin Gastroenterol. 2015;49:212-7.
11. Oyaert M, Vermeersch P, De Hertogh G, Hiele M, Vandeputte N, Hoffman I, et al. Combining antibody tests and taking into account antibody levels improves serologic diagnosis of celiac disease. Clin Chem Lab Med. 2015;53:1537-46.
12. Polanco I, Koester Weber T, Martínez-Ojinaga E, Molina M, Sarria J. Efficacy of a point-of-care test based on deamidated gliadin peptides for the detection of celiac disease in pediatric patients. Rev Esp Enferm Dig. 2017;109:743-8.
13. Lewis NR, Scott BB. Meta-analysis: deamidated gliadin peptide antibody and tissue transglutaminase antibody compared as screening tests for coeliac disease. Aliment Pharmacol Ther. 2010;31:73-81.
14. Werkstetter KJ, Korponay-Szabó IR, Popp A, Villanacci V, Salemme M, Heilig G, et al. Accuracy in diagnosis of celiac disease without biopsies in clinical practice. Gastroenterology. 2017;153:924-35.
15. Wolf J, Petroff D, Richter T, Auth MKH, Uhlig HH, Laass MW et al. Validation of antibody-based strategies for diagnosis of pediatric celiac disease without biopsy. Gastroenterology. 2017;153:410-9.
16. Volta U, Caio G, Boschetti E, Giancola F, Rhoden KJ, Ruggeri E, et al. Seronegative celiac disease: Shedding light on an obscure clinical entity. Dig Liver Dis. 2016;48:1018-22.
17. Molina Arias M, Pérez-Moneo Agapito B. ¿Se podría diagnosticar la enfermedad celíaca solo con serología? Evid Pediatr. 2017;13:56.
18. 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.
19. Hill ID, Dirks MH, Liptak GS, Colletti RB, Fasano A, Guandalini S, et al. Guideline for the diagnosis and treatment of celiac disease in children: recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr. 2005;40:1-19.
20. Gidrewicz D, Potter K, Trevenen CL, Lyon M, Butzner JD. Evaluation of the ESPGHAN Celiac Guidelines in a North American Pediatric Population. Am J Gastroenterol. 2015;110:760-7.

Celiac disease (CD) is an immune-mediated systemic disorder triggered by the consumption of gluten and prolamines in genetically susceptible individuals, and characterised by a variable combination of gluten-dependent clinical manifestations, the presence of specific antibodies, high-risk HLA DQ2 or DQ8 haplotypes and enteropathy.¹

The pathogenic cascade starts in the small intestine, with an enhanced permeability to gluten gliadin and loss of tolerance giving rise to innate and adaptive humoral and cell-mediated immune responses triggered by an external element, gluten, after it is deamidated by tissue transglutaminase type 2 (TTG2), which is the main autoantigen in CD.^2,3

Thanks to the guidelines published by the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) in 2012,¹ it is now possible to diagnose CD in the paediatric population without performance of biopsy as long as patients have obvious symptoms consistent with active CD along with clearly positive (> 10 times the upper limit of normal) antitransglutaminase antibodies, as well as positive antiendomysium antibodies (EMA) in a subsequent test, combined with a high-risk HLA haplotype (DQ2 or DQ8). These guidelines underscore two key aspects:  the systemic nature of the disease, in which enteropathy is considered just one of the elements to consider in diagnosis, and a high-risk HLA haplotype a required factor.

However, the development and application of these guidelines would not have been possible without the currently available serology tools: assays for TTG2 and EMA IgA antibodies, both of which target the same antigen (TTG2). Since enteropathy is no longer considered a necessary criterion for diagnosis, recent efforts have focused on the development and improvement of non-invasive methods and the combination of serologic markers for the diagnosis of CD.

Anti-gliadin antibodies (AGA) of the IgA class have a high sensitivity (Sen) but are also found in healthy individuals and individuals with enteropathies other than CD. Their titres correlate to gluten intake and their presence is considered part of the mucosal immune response. Since the identification of other antibodies (EMA and TTG2 antibodies), the use of AGA has become infrequent and is restricted to children aged less than 2 years, as approximately 10% of those affected in this age group have not yet developed anti-TG2 or endomysial antibodies when CD is first suspected.⁴

The determination of EMA is the most specific method (97-100%), with a positive predictive value (PPV) of 98-100% for the diagnosis of CD. However, it has several technical drawbacks that impede the simultaneous performance of multiple tests, such as its manual processing and its subjective interpretation. Since detection of anti-TG2 by ELISA became available, a much simpler method with almost the same specificity (Spe), determination of EMA is now mainly used to identify potential TTG2 antibody false negatives^4,5 and confirm the positive TTG2 antibody results in a second sample to avoid biopsy, in adherence with the new guidelines.

Determination of TTG2 antibodies is currently the gold standard for diagnosis because while it is less specific (Sen of 91-95% and Spe of 95-97%) than EMA, it can be performed rapidly. Evidence associating TTG2 antibody titres with the degree of histologic damage in CD has existed for years,⁶ even suggesting a directly proportional association between antibody titres and the grade of duodenal histopathology. Patients with TTG2 antibody titres > 100 U/ml have at least Marsh 2 histology, and subsequent studies, prospective⁷ as well as retrospective,^8-10 have found a nearly perfect correlation between anti-transglutaminase antibody titres and the diagnosis of CD confirmed by biopsy, which led the ESPGHAN to establish a minimum of 10 times the reference value to allow the omission of intestinal biopsy.

Later on, evidence emerged on the high affinity of HLA-DQ2/8-restricted T lymphocytes for peptides deamidated by TTG2, a reaction that does not take place in healthy individuals, leading to the analysis of deamidated gliadin peptides (DGP), initially by determination of IgG antibodies with ELISA, with a sensibility (Sen) of 70-95% and a specificity (Spe) of 80-94%. This method is useful in cases in which the diagnostic yield of the TTG2 antibody assay may be lesser, as happens in children aged less than 2 years or with IgA deficiency, but the positive predictive value (PPV) of this test in isolation is low (30%), so its use is not recommended unless it is combined with the determination of TTG2 antibodies or EMA.¹¹ Furthermore, the ESPGHAN guidelines do not currently consider contemplate DGP antibodies. In the past decade, rapid kits for the detection of DGP in capillary blood samples have become commercially available that are useful for initial screening, with a high Sen and Spe and an excellent NPV.¹² Nevertheless, they are not equivalent to the TTG antibody and EMA assays,¹³ so positive results obtained through these kits (or negative results in patients in who there is a strong clinical suspicion) should be confirmed by means of conventional serology.

It is worth highlighting two studies published this year whose aim was to assess the efficacy of serologic testing and the pertinence of the new ESPGHAN guidelines. The first one assessed the efficacy of TTG2 antibodies alone using titres > 10 times the reference value as the criterion for reliable diagnosis and omission of duodenal biopsy in symptomatic patients,¹⁴ and the authors countered the new ESPGHAN guidelines in regard to HLA typing, which they considered unnecessary; the second is the retrospective study reviewed in the current issue of Evidencias en Pediatría comparing the determination of TTG2 antibodies alone to determination of both TTG2 and DGP antibodies.¹⁵ This study also reported excellent positive and negative predictive values for the combination of both assays, although it did not resolve the gaps left by intermediate titres when it comes to the decision whether to perform biopsy in patients with seronegative CD,¹⁶ with associated diseases or risk factors or who are asymptomatic. Furthermore, these results are only reliable in populations where the prevalence is of at least 4%, so they cannot be extrapolated to general populations with lower prevalences, as is the case in Spain, or to asymptomatic patients, which was the conclusion reached by the authors that reviewed this study.¹⁷

This is one of the reasons why duodenal biopsy continues to be the gold standard for diagnosis in adults or, outside Europe,¹⁸ in both children and adults.^19,20

References

1. Husby S, Koletzko S, Korponay-Szabó 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;54:136-60.
2. Kumar J, Kumar M, Pandey R, Chauhan NS. Physiopathology and Management of Gluten-Induced Celiac Disease. J Food Sci. 2017;82:270-7.
3. Koning F. Celiac disease: quantity matters. Semin Immunopathol. 2012;34:541-9.
4. Maglio M, Tosco A, Paparo F, Auricchio R, Granata V, Colicchio B, et al. Serum and intestinal celiac disease-associated antibodies in children with celiac disease younger than 2 years of age. J Pediatr Gastroenterol Nutr. 2010;50:43-8.
5. Giersiepen K, Lelgemann M, Stuhldreher N, Ronfani L, Husby S, Koletzko S, et al. Accuracy of diagnostic antibody tests for coeliac disease in children: summary of an evidence report. J Pediatr Gastroenterol Nutr. 2012;54:229-41.
6. Barker CC, Mitton C, Jevon G, Mock T. Can tissue transglutaminase antibody titers replace small-bowel biopsy to diagnose celiac disease in select pediatric populations? Pediatrics. 2005;115:1341-6.
7. Mubarak A, Wolters VM, Gmelig-Meyling FHJ, Ten Kate FJW, Houwen RHJ. Tissue transglutaminase levels above 100 U/mL and celiac disease: a prospective study. World J Gastroenterol. 2012;18:4399-403.
8. Donaldson MR, Book LS, Leiferman KM, Zone JJ, Neuhausen SL. Strongly positive tissue transglutaminase antibodies are associated with Marsh 3 histopathology in adult and pediatric celiac disease. J Clin Gastroenterol. 2008;42:256-60.
9. Alessio MG, Tonutti E, Brusca I, Radice A, Licini L, Sonzogni A, et al. Correlation between IgA tissue transglutaminase antibody ratio and histological finding in celiac disease. J Pediatr Gastroenterol Nutr. 2012;55:44-9.
10. Singh P, Kurray L, Agnihotri A, Das P, Verma AK, Sreenivas V, et al. Titers of anti-tissue transglutaminase antibody correlate well with severity of villous abnormalities in celiac disease. J Clin Gastroenterol. 2015;49:212-7.
11. Oyaert M, Vermeersch P, De Hertogh G, Hiele M, Vandeputte N, Hoffman I, et al. Combining antibody tests and taking into account antibody levels improves serologic diagnosis of celiac disease. Clin Chem Lab Med. 2015;53:1537-46.
12. Polanco I, Koester Weber T, Martínez-Ojinaga E, Molina M, Sarria J. Efficacy of a point-of-care test based on deamidated gliadin peptides for the detection of celiac disease in pediatric patients. Rev Esp Enferm Dig. 2017;109:743-8.
13. Lewis NR, Scott BB. Meta-analysis: deamidated gliadin peptide antibody and tissue transglutaminase antibody compared as screening tests for coeliac disease. Aliment Pharmacol Ther. 2010;31:73-81.
14. Werkstetter KJ, Korponay-Szabó IR, Popp A, Villanacci V, Salemme M, Heilig G, et al. Accuracy in diagnosis of celiac disease without biopsies in clinical practice. Gastroenterology. 2017;153:924-35.
15. Wolf J, Petroff D, Richter T, Auth MKH, Uhlig HH, Laass MW et al. Validation of antibody-based strategies for diagnosis of pediatric celiac disease without biopsy. Gastroenterology. 2017;153:410-9.
16. Volta U, Caio G, Boschetti E, Giancola F, Rhoden KJ, Ruggeri E, et al. Seronegative celiac disease: Shedding light on an obscure clinical entity. Dig Liver Dis. 2016;48:1018-22.
17. Molina Arias M, Pérez-Moneo Agapito B. ¿Se podría diagnosticar la enfermedad celíaca solo con serología? Evid Pediatr. 2017;13:56.
18. 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.
19. Hill ID, Dirks MH, Liptak GS, Colletti RB, Fasano A, Guandalini S, et al. Guideline for the diagnosis and treatment of celiac disease in children: recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr. 2005;40:1-19.
20. Gidrewicz D, Potter K, Trevenen CL, Lyon M, Butzner JD. Evaluation of the ESPGHAN Celiac Guidelines in a North American Pediatric Population. Am J Gastroenterol. 2015;110:760-7.

Cómo citar este artículo

Martínez-Ojinaga Nodal E. ¿Se acerca el final de la biopsia en la enfermedad celíaca? Evid Pediatr. 2017;13:49.

Cómo citar (eng)

Martínez-Ojinaga Nodal E. Is the use of biopsy in celiac disease coming to an end? Evid Pediatr. 2017;13:49.

Artículos relacionados