The Journal of Pediatrics
Volume 157, Issue 3 , Pages 353-354, September 2010

Diagnosing Celiac Disease: How Important is the Biopsy?

  • Ivor D. Hill, MB, ChB, MD

      Affiliations

    • Corresponding Author InformationReprint requests: Ivor D. Hill, MB, ChB, MD Department of Pediatrics, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157.

Department of Pediatrics, Wake Forest University School of Medicine, Winston-Salem, North Carolina

published online 17 May 2010.

Article Outline

CD, Celiac disease, EMA, Endomysium, GFD, Gluten-free diet, TG2, Tissue transglutaminase

 

See related article, p 373

Celiac disease (CD) is a common condition, with an estimated prevalence of 1% in Western populations. CD is defined as a permanent sensitivity to wheat and related proteins found in barley and rye that occurs in genetically predisposed individuals. It manifests as an immune-mediated enteropathy that shows characteristic changes on intestinal histology.1 With few exceptions, individuals with CD have markers for the HLA-DQ2 genotype and/or -DQ8 genotype and produce antibodies to tissue transglutaminase (TG2) and/or endomysium (EMA).2 The changes seen on intestinal histology are mediated by immune mechanisms involving both the innate and adaptive arms of the immune system,3 and progress from an increase in intraepithelial lymphocytes to crypt hyperplasia and finally progressive villous blunting.4

The diagnosis of CD incurs the recommendation for a life-long strict gluten-free diet (GFD).1 This is not only burdensome and difficult to maintain, but also entails additional costs to the individual and the family. Thus, it is essential that the diagnosis be confirmed before treatment is started. The revised criteria and current guidelines recommend an intestinal biopsy for diagnosing CD.1, 5, 6, 7 The presence of villous blunting (Marsh grade IIIa, IIIb, or IIIc) is strong evidence of the condition.1 The diagnosis is confirmed if complete symptom resolution occurs after implementation of a GFD.5 The absence of villous blunting on histology can be problematic, however, because Marsh grade I and II changes are seen in other conditions as well.8

The advent of serologic tests to screen for CD has expanded our understanding of the protean manifestations of the disease. In addition, screening programs allow us to identify mildly symptomatic or even asymptomatic individuals at an early stage. This has also resulted in the recognition that some symptomatic adults initially fulfill only the criteria for Marsh grade I or II histological changes. In these individuals, continued ingestion of gluten is associated with progression to Marsh grade III on repeat biopsy.9

The report by Kurppa et al in this issue of The Journal now describes similar findings in children.10 Using meticulous morphometric and immunohistochemical analysis of multiple biopsy specimens obtained from the distal duodenum, the authors describe a group of symptomatic, EMA-positive children with either completely normal histology (Marsh 0) or at most Marsh I lesions. These children (study group) were compared with a symptomatic, EMA-positive group diagnosed with CD on the basis of Marsh III lesions (celiac group) and a control group who had symptoms but were EMA-negative and had normal intestinal histology (nonceliac controls). The celiac group was started on a GFD and followed-up with repeat celiac serology testing after 1 year. The GFD option was also offered to those in the study group. Of the 13 children in the study group who were available for long-term follow-up, 8 chose to remain on a regular diet, and the remainder chose the GFD. All children in this group were followed with annual repeat celiac serology, and intestinal biopsy analyses were repeated in those who chose to stay on a regular diet. Children in the nonceliac control group were followed-up with repeat celiac serologic testing after 1 year.

At presentation, there were no differences among the groups in terms of age, sex, symptoms, and family history of CD. Most of the children in the celiac group demonstrated improved symptoms, and all had decreased or normalized EMA and TG2 titers. The 5 children in the study group who chose the GFD demonstrated resolution of clinical symptoms and normalization of EMA and TG2 values. All 8 children in the study group who remained on a regular diet had persistent symptoms with positive serologic tests, and 7 developed small bowel mucosal atrophy within 1-2 years on repeat biopsy. Initiation of a GFD in these cases resulted in subsequent symptom alleviation and normalization of serologic tests, confirming the diagnosis of CD. None of the nonceliac controls had a positive serologic test on repeat testing.

One weakness of this study is that all biopsy samples were obtained from the distal duodenum. Recent reports have indicated that a minority of children initially exhibit the characteristic changes of CD with villous blunting limited to the duodenal bulb and normal histology of the distal duodenum.11, 12 These findings call for reconsideration of current guideline recommendations to include samples from the duodenal bulb in all cases of suspected CD. Had this been done in the present study, it is possible the diagnosis could have been confirmed at the time of initial biopsy in some of those in the study group. On the other hand, a strength of this study was the meticulous methodology used to evaluate the intestinal biopsy specimens, which found significantly higher densities of CD3+ and γδ+ intraepithelial lymphocytes in the study group and the celiac group compared with the nonceliac controls. In addition, all of the children in the study group and the celiac group had TG2-targeted autoantibody deposition in the small intestinal mucosa, whereas this finding was absent in the nonceliac control group. These findings clearly distinguish children with CD from those without CD and could serve as important additional factors in cases where the morphological findings do not initially allow for a positive diagnosis of CD.

Based on the findings of Kurppa et al, the current histology criteria for the diagnosis of CD appear to be inadequate, raising the question of whether biopsy analysis still has a major role in the diagnostic process. Conversely, it could be argued that now more than ever, the intestinal biopsy might be the most important component for the diagnosis to differentiate individuals with CD from those with “gluten sensitivity” not due to CD.

Gluten sensitivity that might not be due to CD is an emerging concept. It is considered in individuals with symptoms, positive serologic tests for CD (usually only antigliadin antibodies), and normal intestinal histology but with symptom improvement after initiation of a GFD. This has most often been described in patients with a variety of neurologic symptoms but may apply to other, nonneurologic symptoms as well.13 It seems likely that some of these cases represent an early stage of CD and will eventually develop characteristic intestinal changes with continued gluten ingestion; however, in others the condition might be mediated through different immunologic mechanisms, as exemplified by some cases of gluten-induced ataxia without the classical HLA markers for CD but with production of antibodies to TG6 as opposed to TG2.13

The major defining feature distinguishing CD from other gluten-induced conditions could be the immunologically mediated effect on the small intestinal mucosa in CD. For this reason, the intestinal biopsy plays a critical role in the diagnosis of CD. Rather than downplay the role of intestinal histology, in future we should be more meticulous in our search for mucosal features that identify CD. This includes obtaining biopsy specimens from the duodenal bulb in all cases, and looking for additional features that allow us to make a diagnosis at an early stage in those who have not yet developed mucosal atrophy. The findings reported by Kurppa et al suggest that CD3+ and γδ+ intraepithelial lymphocyte density and TG2-targeted autoantibody deposition could be useful in this regard.10 Clearly distinguishing between CD and other gluten-sensitive conditions that might not be related to CD is important to our understanding of these conditions. If these conditions are truly unrelated to CD, this raises potential diagnostic, therapeutic, and prognostic implications that will need to be considered in the future.

Back to Article Outline

References 

  1. Hill I, Dirks M, Liptak G, Colletti R, Fasanos 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
  2. Karell K, Louka AS, Moodie SJ, Ascher H, Clot F, Greco L, et al. Hla types in celiac disease patients not carrying the DQA1∗05-DQB1∗02 (DQ2) heterodimer: results from the European Genetics Cluster on Celiac Disease. Human Immunol. 2003;64:469–477
  3. Kagnoff MF. Mucosal inflammation in celiac disease: interleukin-15 meets transforming growth factor β-1. Gastroenterology. 2007;132:1174–1176
  4. Marsh M. Gluten, major histocompatability complex, and the small intestine: a molecular and immunobiological approach to the spectrum of gluten sensitivity (“celiac sprue”). Gastroenterology. 1992;102:330–354
  5. Walker-Smith J, Guandalini S, Schmitz J, Shmerling D, Visakorpi J. Revised criteria for diagnosis of coeliac disease. Arch Dis Child. 1990;65:909–911
  6. Rostom A, Murray J, Kagnoff M. American Gastroenterological Association (AGA) Institute technical review on the diagnosis and management of celiac disease. Gastroenterology. 2006;131:1981–2002
  7. James S. National Institutes of Health Consensus Development Conference on Celiac Disease. Gastroenterology. 2005;128:S1–S9
  8. Kakar S, Nehra V, Murray J, Dayharsh G, Burgart L. Significance of intraepithelial lymphocytosis in small bowel biopsy samples with normal mucosal architecture. Am J Gastroenterol. 2003;98:2027–2033
  9. Kurppa K, Collin P, Viljamaa M, Haimila K, Saavalainen P, Partanen J, et al. Diagnosing mild enteropathy celiac disease: a randomized, controlled clinical study. Gastroenterology. 2009;136:816–823
  10. Kurppa K, Ashorh M, Iltanen S, Koskinen L, Saavalainen P, Koskinen O, et al. Celiac disease without villous atrophy in children: a prospective study. J Pediatr. 2010;157:373–380
  11. Bonamico M, Thanasi E, Mariani P, Nenna R, Luparia R, Barbera C, et al. Duodenal bulb biopsies in celiac disease: a multicenter study. J Pediatr Gastroenterol Nutr. 2008;47:618–622
  12. Weir D, Glickman J, Roiff T, Valim C, Leichtner A. Variability of histological changes in childhood celiac disease. Am J Gastroenterol. 2009;105:207–212
  13. Hadjivassiliou M, Sanders D, Grunewald R, Woodroofe N, Boscolo S, Aeschlimann D. Gluten sensitivity: from gut to brain. Lancet Neurol. 2010;9:318–330

PII: S0022-3476(10)00310-0

doi:10.1016/j.jpeds.2010.04.010

Refers to article:

  • Celiac Disease without Villous Atrophy in Children: A Prospective Study , 19 April 2010

    Kalle Kurppa, Merja Ashorn, Sari Iltanen, Lotta L.E. Koskinen, Päivi Saavalainen, Outi Koskinen, Markku Mäki, Katri Kaukinen
    The Journal of Pediatrics September 2010 (Vol. 157, Issue 3, Pages 373-380.e1)

The Journal of Pediatrics
Volume 157, Issue 3 , Pages 353-354, September 2010

Article Tools